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Dissertations / Theses on the topic 'Bioisosterie'
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1
MORIN, ISABELLE. "3-aryl as-triazines : bioisosterie avec les 6-aryl pyridazines." Université Louis Pasteur (Strasbourg) (1971-2008), 1991. http://www.theses.fr/1991STR13021.
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Un examen comparatif de bioisosteres potentiels de derives pyridaziniques (pyrazines, pyrimidines, 1,3,4-thiadiazoles, et 1,2,4-triazines) a ete realise. Les structures etablies par diffraction aux rayons x suivies de calculs semi-empiriques ont mis en evidence l'importance du moment dipolaire comme critere de differenciation entre ces differents systemes heterocycliques. Le systeme as-triazinique, predit comme devant etre bioequivalent des pyridazines a ete plus particulierement etudie. Sur le plan chimique, des ameliorations ont ete apportees a leur synthese au depart de derives d'hippurate d'ethyle. La reactivite du systeme a egalement ete etudiee, en particulier par la mise au point d'aminoalkyltriazines et de triazolotriazines. Une vingtaine d'aminoalkyltriazinones ont ete etudiees pour leurs proprietes analgesiques. Les affinites micromolaires de ces derives envers les recepteurs opiaces sigma et kappa concordent avec les valeurs moderees observees sur des tests d'analgesie chez l'animal. Des predictions d'activite inhibitrice de l'acetylcholinesterase pour des alkylaminotriazines se sont averees verifiees et demontrent a nouveau la bioequivalence entre les triazines et les pyridazines et l'absence de bioequivalence entre la pyrazine et les pyridazines. Au depart d'une dizaine de molecules synthetisees, plusieurs se sont revelees interessantes comme inhibiteur competitif et reversible de l'acetylcholinesterase; la plus puissante montrant une ic#5#0 de 3. 10#-#7 m
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Nguyen, Binh. "Synthese siliciumorganischer Wirkstoffe und Beiträge zur Methodenentwicklung zum Aufbau von Silazepan- und Silapyrrolidin-Derivaten." kostenfrei, 2009. http://www.opus-bayern.de/uni-wuerzburg/volltexte/2009/3550/.
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Büttner, Matthias Werner. "Synthese neuartiger siliciumorganischer Pharmaka und Riechstoffe sowie siliciumhaltiger Synthesebausteine." kostenfrei, 2007. http://www.opus-bayern.de/uni-wuerzburg/volltexte/2008/2404/.
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Delacroix-Beaurain, Nathalie. "Conception et synthese de derives benzothiopheniques impliquant les mecanismes melatoninergiques." Lille 2, 2001. http://www.theses.fr/2001LIL2P254.
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Keller, Max. "Guanidine-acylguanidine bioisosteric approach to address peptidergic receptors : pharmacological and diagnostic tools for the NPY Y1 receptor and versatile building blocks based on arginine substitutes." kostenfrei, 2008. http://www.opus-bayern.de/uni-regensburg/volltexte/2009/1111/.
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Schmid, Thomas. "Darstellung von Sila-Analoga und siliciumhaltigen Derivaten von Wirk- und Riechstoffen sowie [alpha]-Aminosäuren [Alpha-Aminosäuren] im Rahmen von Untersuchungen zur C-Si-Bioisosterie." [S.l. : s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=973410582.
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Statham, Matthew Alexander John. "Silanediols as Carbonyl Group Bioisosteres." Thesis, University of Newcastle Upon Tyne, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.489291.
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Choy, Alison Pui Ki. "Prediction of metabolic stability and bioavailability with bioisosteric replacements." Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/278798.
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Drug development is a long and expensive process. Potential drug candidates can fail clinical trials due to numerous issues, including metabolic stability and efficacy issues, wasting years of research effort and resource. This thesis detailed the development of in silico methods to predict the metabolic stability of structures and their bioavailability. Coralie Atom-based Statistical SOM Identifier (CASSI) is a site of metabolism (SOM) predictor which provides a SOM prediction based on statistical information gathered about previously seen atoms present in similar environments. CASSI is a real-time SOM predictor accessible via graphical user interface (GUI), allowing users to view the prediction results and likelihood of each atom to undergo different types of metabolic transformation. Fast Metabolizer (FAME)1 is a ligand-based SOM predictor developed around the same time by Kirchmair et al. In the course of the evaluation of CASSI and FAME performance, the two concepts were combined to produce FamePrint. FamePrint is a tool developed within the Coralie Cheminformatics Platform developed by Lhasa Limited. which can carry out SOM predictions, as well as bioisosteric replacement identification. Same as CASSI, this is available via the Coralie application GUI. The bioavailability issues caused by the metabolic enzyme, cytochrome P450 3A4, and transporter protein P-gylcoprotein are also investigated in this work, along with the potential synergistic relationship between the two systems. In silico classifiers to distinguish substrates against non-substrates of the two systems are produced and it was envisaged that these classifiers can be integrated into FamePrint as an additional layer of information available to the user when deciding on bioisosteric replacements to use when optimising a compound.
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Burt, Catherine. "A theoretical investigation of bioisosterism by molecular similarity." Thesis, University of Oxford, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.291094.
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Schmitz, Johannes. "Derivate und Bioisostere des Acetylcholins und deren Aktivität am nikotinischen Acetylcholin-Rezeptor." [S.l. : s.n.], 2002. http://deposit.ddb.de/cgi-bin/dokserv?idn=966355792.
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Wöge, Sonja [Verfasser]. "Potenzielle Krebstherapeutika mit Salicyloyl- und bioisosteren Chinazolin-Teilstrukturen / Sonja Wöge." Berlin : Freie Universität Berlin, 2008. http://d-nb.info/1022940139/34.
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Höhfeld, Kerstin. "A chemoinformatics approach to identify bioisosteric scaffold replacements in compounds of PubChem bioassays." kostenfrei, 2009. http://d-nb.info/100125385X/34.
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Lin, Yih-Shyan. "Bioisosteres of phosphate and pyrophosphate ligands as inhibitors of therapeutic targets." Thesis, McGill University, 2014. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=123221.
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Part IHuman farnesyl pyrophosphate synthase (hFPPS) represents a critical enzyme which controls the first branch point of mevalonate pathway. It catalyzes the consecutive condensations of dimethylallyl pyrophosphate (DMAPP) with two molecules of isopentenyl pyrophosphate (IPP) to generate farnesyl pyrophosphate (FPP), a vital metabolite for protein prenylation. Nitrogen-containing bisphosphonates (N-BPs), a class of hFPPS inhibitors targeting the allylic sub-pocket, have been approved for the treatment of bone resorptive diseases. They also exhibit direct and indirect anti-cancer effects in vitro and are considered as potential anti-malignant agents. However, they suffer from poor pharmaceutical properties, such as low bioavailability and tissue distributions, due to their negatively charged nature. In this study, several approaches have been explored to identify hFPPS inhibitors with improved biopharmaceutical properties. Increasing the overall lipophility of the inhibitors by modifying them with hydrophobic moieties was first investigated. Some biological experiments were performed to demonstrate their inhibition activity, anti-proliferation effects, and potential mechanism of action. X-ray crystallography was employed to reveal the novel structural rearrangements of hFPPS upon binding with one of our potent inhibitors. Moreover, less charged hFPPS allosteric inhibitors, such as sulfonylphosphoryamidic and monophosphonate derivatives, were explored as well. Several analogs were shown to exhibit moderate activity toward inhibiting hFPPS and considered as potential novel hits for further investigations. Furthermore, employment of pro-drug strategies to improve the biopharmaceutical characters is also discussed. Part IIPyrophosphate (PPi) is the by-product generated during nucleotide polymerization. Foscarnet, a PPi bioisostere, has been shown to inhibit HIV reverse transcriptase (RT) by trapping the HIV RT/DNA complex in the pre-translocational state. The bisphoshphonate moiety is structurally similar to PPi and represents a potential pharmacophore for the design of HIV RT inhibitors. Hybrids of the bisphosphonate moiety and pyridopyrimidines, that are known purine mimics, were designed as potential HIV RT inhibitors. Several analogs were shown to inhibit DNA polymerization catalyzed by RT at low micromolar ranges and considered as potential new chemotypes for further investigation.Partie ILa synthase farnésyl-pyrophosphate humaine (FPPSh) représente une enzyme essentielle qui contrôle le premier point de dérivation de la voie du mévalonate. Elle catalyse les condensations consécutives du diméthylallyl-pyrophosphate (DMAPP) avec deux molécules d'isopentényl-pyrophosphate (IPP) afin de produire la farnésyl-pyrophosphate (FPP), un métabolite nécessaire pour la prénylation de plusieurs protéines. Les bisphosphonates contenants un groupe d'azote (N-BPs), une famille des inhibiteurs qui visent la sous-poche allylique de la FPPSh, ont été approuvés pour le traitement des maladies qui causent la résorption des os. Ils présentent aussi un effet direct ainsi qu'indirect anti-cancer in Vitro et sont considérés comme des agents anticancéreux potentiels. Cependant, ils ont un mauvais profile pharmaceutique, ainsi qu'une mauvaise biodisponibilité et exposition des tissus, en raison de leur nature anionique. Dans cette étude, plusieurs façons ont été explorées pour identifier les inhibiteurs de la FPPSh avec des propriétés biopharmaceutiques améliorées. Premièrement, une investigation pour rendre les inhibiteurs moins polairs en ajoutant des groupes hydrophobiques a été poursuivie. Puis, des expérimentes biologiques pour démontrer leur efficacité d'inhibition, effet anti-prolifération, et mécanisme d'action potentielle. La cristallographie à rayons X a été utilisée pour démontrer le changement en conformation de la FPPSh occupé par notre inhibiteur plus actif. En plus, des inhibiteurs de la FPPSh moins anioniques, comme des dérivatifs sulfonophosphoamidiques et monophosphonatiques, ont été explorés. Quelques analogues ont été démontrés d'avoir une inhibition modérée vers FPPSh et pouvant être considérés comme inhibiteurs potentiels avec plus d'investigation. En outre, l'emploi d'une approche prodrogue pour améliorer les propriétés biopharmaceutiques a été faite. Partie IILa pyrophosponate (PPi) est un sous-produit généré dans la polymérisation des nucléotides. Le foscarnet, une bioisostère de la PPi, a été prouvé de terminer la polymerisation des nucleotides par la transcriptase inverse (RT) VIH en trappant la complexe RT VIH/ADN dans l'état pretranslocational. La bisphosphonate ressemble à la structure de la PPi et représente une pharmacophore potentielle pour la conception des nouveaux inhibiteurs pour la RT. Les hybrides du groupe bisphosphonate avec les dérivatifs pyridopyrimidines, les mimiques purines, ont été conçus comme des inhibiteurs potentiels de la RT VIH. Quelques analogues ont été démontrés pour inhibir la polymérisation de l'ADN catalysé par RT VIH dans le genre faible micromole et sont considérés comme des échafaudages potentiels pour des futures investigations.
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CHAYER, SAID. "Bioisosteres des 3-alkylamine pyridazines : synthese et proprietes inhibitrices de l'acetylcholinesterase." Université Louis Pasteur (Strasbourg) (1971-2008), 1994. http://www.theses.fr/1994STR13237.
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Les 3-aminoethylaminopyridazines, analogues structuraux de la minaprine, constituent une classe pharmacologique importante. En particulier, certaines d'entre elles facilitent la neurotransmission cholinergique et l'un d'entre eux est actuellement etudie chez l'homme, pour le traitement de la maladie d'alzheimer. L'objectif de cette these etait d'etudier plus particulierement les possibilites de remplacement du cycle pyridazine dans ces composes par d'autres systemes bioisosteres (pyridines, triazines, dihydrotriazines). La cible pharmacologique visee au cours de ce travail est l'acetylcholinesterase (ache), enzyme responsable de la degradation de l'acetylcholine. Ceci nous a amene a etudier plus en detail les proprietes oxydo-reductrices des triazines, en particulier l'aromatisation des dihydrotriazinones par deprotonation. D'autre part, la synthese des 3-aminopyridazines est rendue delicate du fait de la faible reactivite des intermediaires de synthese (3-chloropyridazines). L'introduction reversible d'un groupe cyano en position 4 sur de tels systemes augmente tres sensiblement leur pouvoir electrophile. Cette observation a permis de mettre au point une methode plus versatile (rapport stoechiometrique, conditions de reaction plus douces) des 3-alkylaminopyridazines. Au plan pharmacologique, nous avons obtenu un derive environ trois cent fois plus puissant que la minaprine comme inhibiteur de l'ache
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Bhandare, Richie R. "Investigation into the bioisosteric approach in the design, synthesis and evaluation of muscarinic receptor ligands." Diss., Temple University Libraries, 2013. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/214985.
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Pharmaceutical SciencesPh.D.
The acetylcholine (ACh) receptor system belongs to rhodopsin GPCR family and is an integral membrane protein divided into two types: muscarinic and nicotinic. The naturally occurring neurotransmitter acetylcholine binds to these two receptor systems non- selectively. The regulatory effects of the neurotransmitter acetylcholine are diverse ranging from autonomic nervous system and the central nervous system through different types of neurons innervated by cholinergic inputs. Muscarinic acetylcholine receptors (mAChRs) are divided into five receptor subtypes (M1-M5). In general, M1, M3 and M5 receptor subtypes are coupled via Gq like proteins; while M2 and M4 subtypes are coupled to Gi-proteins. Muscarinic receptors are widely distributed in the body where they mediate a variety of important physiological effects. mAChRs have been the target of drug development efforts for the treatment of various disorders including overactive bladder, Alzheimer's disease, pain, cognitive impairment, drug addiction, schizophrenia and Parkinson's disease. The development subtype selective ligands possess a challenge due to a high degree of homology among mAChR subtypes, however the recent availability of the X-ray crystal structure for the M2 and M3 receptor can be utilized for the design of new ligands. The pharmacophoric requirements for cholinergic ligands have been reported by numerous investigators based on structure-activity relationship (SAR) and/or molecular modeling data of known muscarinic ligands. These fundamental requirements are useful when designing muscarinic ligands but have provided little guidance in the design of subtype selective compounds. Our interest in developing novel muscarinic receptor ligands led to the design of lactone-based ligands using an approach similar to that reported by Kaiser et al. Preliminary binding studies of our previously synthesized lactone based compounds indicated that several were nonselective, low affinity (IC50 = µM range) muscarinic agonists (based on preliminary in vivo data). Hence based on the background information, we decided to utilize the previously synthesized lactone parent compound as lead molecule set out to investigate a new series of lactone based compounds in order improve the affinity and later the selectivity of ligands. Bioisosteric approach has been investigated for the metabolic lability of the lactone ring. Four probable bioisosteres have been evaluated: tetrahydrofuran, 1,3-benzodioxole, oxazolidinone and chromone. Thermal/microwave assisted synthesis has been utilized in the generation of intermediates as well as final compounds. Preliminary screening and further evaluation (IC50/ subtype selectivity) has resulted in the identification of promising fragments as bioisosteres for the lactone ring.
Temple University--Theses
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Schwarz, Simone. "Design, Synthese und 3D-QSAR-Analysen neuer nAChR-Liganden : Bioisostere der Alkaloide (+)-Anatoxin-a und (-)-Ferruginin /." Marburg : Görich & Weiershäuser, 2002. http://www.gbv.de/dms/bs/toc/372549241.pdf.
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Ivanova, Maria. "New access to difluoromethylphosphonate-containing molecules : via a copper-mediated approach." Thesis, Normandie, 2017. http://www.theses.fr/2017NORMIR14.
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Depuis des décennies, la chimie du fluor est un domaine suscitant un fort intérêt. Bien que de nombreuses méthodologies originales et élégantes aient été développées pour introduire des groupements fluorés variés, le résidu CF2PO(OEt)2 reste encore peu étudié. Cela contraste avec ses propriétés uniques et à hautes valeurs ajoutées. En effet, le motif CF2PO(OEt)2 s'est avéré être un bioisostère métaboliquement stable du groupement phosphate, ce dernier étant particulièrement instable in vivo en comparaison. En conséquence, des approches pour incorporer ce motif au sein de molécules ont été développées bien qu'encore limitées à un nombre restreint de transformations. Dans le cadre de cette thèse, nous souhaitons proposer une méthode générale et directe pour accéder à des molécules contenant le groupement CF2PO(OEt)2. La première partie de cette thèse a été dédiée à l'introduction du motif CF2PO(OEt)2 sur des sels d'iodonium comportant un substituant aryle, heteroaryle, ou dérivés d'alcènes et d'alcynes, mettant en jeu la génération d'une espèce de type CuCF2PO(OEt)2 (Chapitre II). Puis, l'utilité et la généralité de cette transformation a été démontrée lors de la fonctionnalisation de dérivés de type R-X (R = vinyle, allyle et benzyle) ainsi que des disulfures en tant qu'électrophiles. Par ailleurs, une réaction de couplage de type Ullmann réalisée à température ambiante a été étudiée. Finalement, la réactivité divergente de l'espèce CuCF2PO(OEt)2 envers les α-diazoesters, par un simple changement du sel de cuivre, a été examinée (Chapitre III). Cette approche a été étendue par la suite aux dérivés d'α-bromocétones afin d'offrir une voie d'accès aux cétones contenant un motif SCF2PO(OEt)2 en position α (Chapitre IV)Since several decades, the organofluorine chemistry is a research area of strong interest. While plenty of original and elegant methodologies were developed to introduce various fluorinated groups, the CF2PO(OEt)2 residue was scarcely spotlighted. This contrasts with its unique and highly valuable properties. Indeed, the CF2PO(OEt)2 moiety proved to be a metabolically stable bioisoster of the in vivo unstable phosphate group. As a result, approaches to incorporate this motif onto molecules were developed albeit still restricted to few transformations. In this PhD thesis, we would like to propose a general and straightforward method to access CF2PO(OEt)2-containing molecules. A first part was dedicated to the introduction of the CF2PO(OEt)2 motif on aryl, heteroaryl, vinyl and alkynyl iodonium salts, by generating the CuCF2PO(OEt)2 species (Chapter II). Then, the utility and the generality of this transformation were further demonstrated using R-X (R = vinyl, allyl and benzyl) as well as disulfides as the electrophiles. Besides, a Ullmann-type cross-coupling reaction proceeding at room temperature was also studied. Finally, the divergent reactivity of the CuCF2PO(OEt)2 species toward α-diazoesters, by a simple change of copper salt, was investigated (Chapter III). This approach was then extended to α-bromoketone derivatives to access the a-SCF2PO(OEt)2 ketones (Chapter IV)
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Green, Anthony James. "Computation of hydrogen bond basicity as a descriptor in bioisosterism : a quantum chemical topology perspective." Thesis, University of Manchester, 2013. https://www.research.manchester.ac.uk/portal/en/theses/computation-of-hydrogen-bond-basicity-as-a-descriptor-in-bioisosterism-a-quantum-chemical-topology-perspective(068da139-48b0-4881-a131-5c281fd4af8a).html.
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Hydrogen bonding is a regularly occurring non covalent interaction in biological systems. Hydrogen bonding can influence a drug’s interaction with its target. It is therefore important to practically measure the relative strengths of hydrogen bonds. Hydrogen bond basicity is a measure of a hydrogen bond acceptor’s capacity to accept hydrogen bonds. There are many hydrogen bond basicity scales. However, the pKBHX scale is claimed to be the most relevant to medicinal chemists because it gives a thermodynamically deducible values for each site in polyfunctional bases. A computed property, the change in energy of the hydrogen bond donor hydrogen bond atom ΔE(H), derived from the quantum theory of atoms in molecules has been found to correlate strongly with pKBHX values for OH and NH hydrogen bond donors. In particular, R2 values of 0.95 and 0.97 have been found when methanol and methylamine respectively are used as hydrogen bond donors. The property ΔE(H) has also been successfully used to predict the pKBHX values of an external data set and the values of polyfunctional bases. The strength of the correlations are not dramatically affected by using scaled down fragments of bases, or by relaxing the convergence criteria during the geometry optimisation step of calculations. The relationship between ΔE(H) and pKBHX has been found to break down for tertiary amines, and more generally for strong proton acceptors with pKBH+ values greater than 6. The successful pKBHX prediction model was, however, unsuccessful in predicting drug binding data and pKBHX values of bases that accept two separate hydrogen bonds. At this moment in time both the reason why the relationship between pKBHX and ΔE(H) is present and then breaks down for strong proton acceptors is unfortunately unknown.
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Brennauer, Albert. "Acylguanidines as bioisosteric groups in argininamide-type neuropeptide Y Y₁ and Y₂ receptor antagonists synthesis, stability and pharmacological activity /." [S.l.] : [s.n.], 2006. http://deposit.ddb.de/cgi-bin/dokserv?idn=982416962.
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Armand, Jeremy Richard. "Late Stage Functionalization of 1,2-Azaborines for Application in Biomedical Research:." Thesis, Boston College, 2019. http://hdl.handle.net/2345/bc-ir:108646.
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Thesis advisor: Shih-Yuan . LiuChapter 1. Use of boron as a pharmacophore is as growing but still underdeveloped strategy for expanding chemical space in biomedical research. In addition to more established methods of incorporating boron in drug development, an attractive and emerging method of introducing boron into biologically active compounds is through boron-nitrogen containing heterocycles. In particular, the Liu group has focused on exploring the interactions of monocyclic 1,2-azaborines in biological space. In order to install complicated chemical functionality needed for further studies, methods for late stage functionalization of 1,2-azaborines must be developed. Described herein is a method for functionalizing 1,2-azaborine at the C3- and C5-positions, with bromine and iodine handles, respectively. Chapter 2. Described is the application of the turbo Grignard reaction to 1,2-azaborines bearing a B–Cl bond. The reaction utilizes iPrMgCl·LiCl to form aryl carbon nucleophiles and is tolerant of sensitive functional groups such as nitriles and esters. Development of the reaction obviates the need to use toxic organotin reagents to install aryl groups at the B-position that bear sensitive, electrophilic functionalities
Thesis (MS) — Boston College, 2019
Submitted to: Boston College. Graduate School of Arts and Sciences
Discipline: Chemistry
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Pluym, Nikola [Verfasser], and Armin [Akademischer Betreuer] Buschauer. "Application of the guanidine–acylguanidine bioisosteric approach to NPY Y2 receptor antagonists: bivalent, radiolabeled and fluorescent pharmacological tools / Nikola Pluym. Betreuer: Armin Buschauer." Regensburg : Universitätsbibliothek Regensburg, 2011. http://d-nb.info/1023276062/34.
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Thorstensson, Fredrik. "Structure-Based Design and Synthesis of Protease Inhibitors Using Cycloalkenes as Proline Bioisosteres and Combinatorial Syntheses of a Targeted Library." Doctoral thesis, Linköping : Linköpings universitet, 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-4938.
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Tavares, Mauricio Temotheo. "Candidatos a novos agentes antineoplásicos: síntese e avaliação da atividade antitumoral de análogos sulfonatos e sulfonamídicos da capsaicina." Universidade de São Paulo, 2014. http://www.teses.usp.br/teses/disponiveis/9/9138/tde-29102014-153643/.
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O câncer é o segundo grupo de doenças que mais mata em todo o mundo, atrás apenas das doenças cardiovasculares. No Brasil, esse panorama é preocupante devido ao período de acentuada tendência de envelhecimento, fase etária de maior incidência do câncer. Neste contexto, a atual terapia antineoplásica continua apresentando diversos vieses quanto à toxicidade e seletividade. Muitos dos fármacos empregados na clínica médica são de origem natural, ou tiveram em suas etapas iniciais de desenvolvimento, correlação com produtos naturais, enaltecendo a importância de fontes naturais no desenvolvimento de novos compostos bioativos. A capsaicina, substância responsável pela pungência apresentada pelos frutos de pimenteiras do gênero Capsicum, tem se mostrado um importante agente natural com atividade citotóxica à diversas linhagens neoplásicas, porém, sua ação pungente e baixa estabilidade físico-química, limitam seu emprego terapêutico. Com isso, a capsaicina apresenta grande potencial em servir como arcabouço para o planejamento de novas entidades químicas bioativas, análogas à mesma, para emprego no tratamento do câncer. Este trabalho propôs-se a planejar e sintetizar análogos sulfonamídicos e sulfonatos da capsaicina, promovendo variações moleculares no núcleo estrutural capsaicinóide. Após síntese em única etapa, os análogos foram obtidos e caracterizados por faixa de fusão, RMN 1H/13C e análise elementar. Posteriormente os compostos foram submetidos a ensaio de citotoxicidade nas linhagens tumorais: MDA-MB-231 e MCF-7 (de câncer de mama), B16-F10 (melanoma murino) e sobre linhagens sadias de fibroblasto (3T3), pelo método de avaliação da viabilidade celular por biorredução do sal de tetrazólio, o MTT. Quatro compostos apresentaram atividade biológica interessante, em concentrações micromolares (µM) iferiores à atividade apresentada pela capsaicina, destacando-se os compostos RPF-101 e RPF-151, os mais ativos e que tiveram seus mecanismos de indução de morte investigados. Estudos teóricos subsequentes realizados com os análogos de maior atividade (RPF-101 e RPF-151), revelaram que as modificações moleculares promovidas nas estruturas dos mesmos conferiram maior caráter hidrofílico e maior momento de dipolo, o que pode estar relacionado com o incremento na atividade biológica de ambos. A avaliação dos compostos ativos frente às propriedades constantes na Regra dos Cinco de Lipinski (RO5) revelou que estes respeitam todos os parâmetros da regra, enaltecendo assim o caráter druglikeness dos mesmos, em serem ativos via administração oral, visto que o RPF151 não apresentou ação pungente in vivo. A obtenção dos compostos RPF-101 e RPF-151 indicam o sucesso alcançado com a otimização estrutural promovida no arcabouço capsaicinóide, e enaltece o potencial destes análogos em inspirar o planejamento de novas estruturas, ainda mais otimizadas, que possuam maior potência e menor toxicidade associada.Cancer is the second most lethal group of diseases all over the world, just behind cardiovascular diseases. This scenery is worrying in Brazil due the pronounced aging trend observed, that presents the higher incidence of cancer. In this context, the current anticancer therapy still have several biases regarding toxicity and selectivity. Many current medicines correlate to natural products, even in its early stages of development, which highlight the importance of natural sources in the design of new bioactive compounds. Capsaicin is the substance responsible for the pungency of Capsicum genus\' chili peppers. Capsaicin has been shown as an important natural agent because of its cytotoxic activity against several tumor cell lines. However, the pungency and poor stability presented by capsaicin restricts its therapeutic employments. Thus, the capsaicinoid scaffold has a great potential to inspire the design of new bioactive analog entities to be employed in anticancer therapy. This project aimed at designing and synthesizing sulfonamide and sulfonate analogues of capsaicin, performing molecular changes on capsaicinoid core. After a single step synthesis, the analogues were purified and characterized by melting point, 1H/13C NMR and elementary analysis. Subsequently, cytotoxicity assays were performed by MTT method on tumor cell lines MDA-MB-231 and MCF-7 (breast cancer), B16-F10 (murine melanoma) and on healthy fibroblast (3T3). Four compounds showed interesting biological activity at micromolar concentrations (µM) and their IC50 were lower than that presented by capsaicin. The most active compounds, RPF-101 and RPF-151, had their death induction mechanisms investigated. In silico subsequent studies with the most active compounds (RPF-101 and RPF-151) showed that molecular changes promoted on each one increased their hydrophilicity and raised their dipole moment, which may be related to the improvement on biological activity of both. The evaluation of active compounds for Lipinski´s Rule of Five (RO5) properties revealed that they respect all properties presenting its druglikeness for oral administration since RPF151 did not presented in vivo pungency. The RPF-101 and RPF-151 indicate the success obtained by the structural optimization promoted on capsaicinoid scaffold and emphasizes the potential of these analogues to inspire the designing of new future optimized structures, with greater potency and less associated toxicity.
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Rennar, Georg Alexander [Verfasser], and Martin [Akademischer Betreuer] Schlitzer. "Antischistosomal-aktive Dithiocarbamat-Derivate unter besonderer Berücksichtigung von Nitrogruppen-Bioisosteren und der Schwefelsäurediamid-Teilstruktur - Synthese und in-vitro-Testung - / Georg Alexander Rennar ; Betreuer: Martin Schlitzer." Marburg : Philipps-Universität Marburg, 2021. http://d-nb.info/1241246661/34.
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Fernandes, Thais Batista. "Planejamento, síntese e avaliação do potencial antitumoral de compostos arilsulfonil-hidrazônicos." Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/9/9138/tde-01102015-134701/.
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A capsaicina é um componente pungente das pimentas do gênero capsicum que possui atividade antitumoral. Na busca por compostos antineoplásicos mais eficazes e seletivos em relação aos disponíveis atualmente, foi desenvolvido um análogo sulfonamídico sintético da capsaicina, o RPF101, que apresentou atividade citotóxica superior em linhagens de adenocarcinoma de mama. Face ao exposto, o objetivo deste trabalho foi otimizar a atividade do RPF101 a partir da síntese de análogos sulfonil-hidrazônicos planejados por bioisosterismo. Treze análogos foram sintetizados em três etapas, baseando-se na reação entre cloreto de sulfonila e hidrato de hidrazina para obtenção do intermediário sulfonil-hidrazida; oxidação do álcool piperonílico para obtenção do piperonal; e reação de adição nucleofílica entre sulfonil-hidrazida e piperonal ou vanilina, que apresentaram rendimentos entre 23 e 85%. Os compostos foram caracterizados por metodologias de RMN 1H/13C, faixa de fusão e análise elementar e avaliados quanto sua capacidade citotóxica em células de adenocarcinoma de mama (MDA-MB-231 e MCF-7) pelo método do MTT. Dois análogos mostraram-se ativos nas duas linhagens, dos quais o mais promissor, RPF906 (IC50 em MDA-MB-231 = 104,6 µM) foi submetido a estudos de elucidação mecanística, onde observou-se indução de apoptose, causando interrupção do ciclo celular na fase G0/G1. Os resultados obtidos mostraram que o grupo benzodioxol favorece a atividade biológica quando comparado ao grupo metilcatecol. Estudos de modelagem molecular sugerem que uma maior hidrofilicidade esteja relacionada com uma atividade superior. Embora menos ativas que seu protótipo, as sulfonil-hidrazonas apresentaram efeito biológico e mostram-se promissoras no desenvolvimento de compostos com potencial antitumoral. Novas modificações moleculares devem ser planejadas com o intuito de otimizar a atividade e seletividade destes compostos.Capsaicin is a primary pungent compound in red peppers, which has antitumor activity. In view of demand for more selective and less toxic anticancer agents, our group reported a synthetic sulfonamide capsaicin-like analogue, RPF101, which presents higher cytotoxicity in adenocarcinoma cell line than its prototype. Thus, the aim of this work is to optimize RPF101 activity by the synthesis of sulfonylhydrazone analogues, using the bioisosterism as molecular modification strategy. Thirteen analogues were synthesized in three reaction steps: oxidation of piperonyl alcohol to the piperonyl aldehyde; nucleophilic substitution reaction between sulfonyl chloride and hydrazine hydrate to obtain the intermediate sulfonylhydrazide; nucleophilic addition reaction between sulfonylhydrazide and piperonal of vanilin to obtain sulfonylhydrazones, which showed yields between 23 and 85%. All compounds were characterized by NMR 1H/13C, melting point and elemental analisys and evaluated for their cytotoxic activity in breast tumor cell lines (MDA-MB-231 and MCF-7). Two analogues showed cytotoxic effect although RPF906 (IC50 in MDA-MB-231= 104.6 µM) had been the most promising and was further evaluated about its mechanistic properties. This compound induced apoptosis and cell cycle arrest at the G0/G1 phase. Results showed that the introduction of benzodioxol group increases cytotoxicity. Molecular modeling studies suggests that superior hydrophilicity is related to superior activity. Sulfonyl-hydrazone analogues were less cytotoxic than their prototype, but they are still promising compounds. Molecular modifications strategies should be done to optimize the activity and selectivity of these compounds.
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Gatti, Fernando de Moura. "Síntese e avaliação biológica de sulfonil-hidrazonas análogos do nitrofural como candidatos a antichagásicos." Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/9/9138/tde-11092015-160545/.
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A Doença de Chagas é uma protozoose causada pelo parasita hemoflagelado Trypanosoma cruzi. Classificada pela Organização Mundial de Saúde como extremante negligenciada, essa doença é endêmica em 21 países da América Latina, entretanto podem ser encontrados, ainda, casos nos EUA, Canadá, Europa e Japão devido a movimentos migratórios. Segundo estimativa da Organização Mundial da Saúde, no ano de 2012 havia de 8 a 10 milhões de pessoas infectadas mundialmente e cerca de 25 milhões de pessoas sob risco de contrair a doença de Chagas, ainda sim, havia a ocorrência de 56 mil novos casos da doença e cerca de 12 mil mortes por ano, recorrente de complicações da doença. Diante destes números, essa parasitose se apresenta com um sério problema de saúde pública mundial. A terapêutica antichagásica disponível apresenta apenas dois fármacos o Nifurtimox e o Benznidazol, que atuam somente na fase aguda da doença e provocam sérios efeitos adversos, sendo necessária a busca por novos fármacos eficazes contra o parasita. Os métodos modernos de planejamento de fármacos antiparasitários envolvem a seleção de vias metabólicas específicas a serem bloqueadas, nesse contexto se encontram diferentes proteases, enzimas envolvidas em processos essenciais para a sobrevivência do parasita, entre elas a cruzaína, principal cisteíno-protease do T. cruzi, a qual é responsável pela sobrevivência, replicação celular e invasão do parasita à célula hospedeira, se apresentando como um excelente alvo bioquímico na pesquisa de novos agentes antichagásicos. Partindo do estudo do nitrofural (5-nitro-2-furfurilidenossemicarbazona), antibacteriano também conhecido por sua ação inibitória da cruzaína, adotamos-o como protótipo na pesquisa de fármaco contra a doença. No presente trabalho, utilizou-se o bioisosterismo como estratégia de modificação molecular no planejamento de compostos antichagásicos, inibidores da cruzaína. Foram sintetizados 27 derivados sulfonil-hidrazônicos, para os quais foi determinada a pureza por CLAE e caracterizados por faixa de fusão, espectroscopia no UV e RMN 1H e RMN 13C. Os compostos sintetizados foram avaliados frente às formas celulares epimastigota do T. cruzi, apresentando atividade inibitória de crescimento celular entre 20 e 100% a 100 µM. Nos ensaios frente a cruzaína, os derivados nitrados se mostraram ativos com IC50 em torno de 100 µM. Visto os resultados, podemos sugerir que o grupo nitro presente em alguns compostos pode ser o responsável pela atividade tripanomicida. Face a indicação de toxicidade do grupo nitro, os derivados não nitrados, Ie, IIf e IIIe, podem ser considerados promissores, visto sua atividade intermediária como tripanomicida, entre 45 e 60% à 100 µM, sendo que o composto IIf também apresentou atividade inibidora da cruzaína, 23,4% à 100 µM, podendo assim serem utilizados como ponto de partida na busca de eficazes agentes antichagásicos.Chagas disease, a protozoonosis caused by the hemoflagellate parasite Trypanosoma cruzi, is classified as an extremely neglected disease by World Health Organization. It is an endemic disease in 21 countries on Latin America and cases in the USA, Canada, Europe and Japan were also reported as a consequence of migratory activity. In the last five years, it is estimated that around 8 to 10 million people worldwide were affect by this disease, with nearly 12,000 deaths due to disease complications and approximately 25 million people being at risk of contracting it. Chagas disease is therefore a worldwide public health problem. There are only two available antichagasic therapeutic drugs, nifurtimox and benznidazol, which act only in the acute phase of the disease and cause serious adverse effects, making it necessary to search novel, more effective drugs against this parasite. The newer methods of antiparasitic drug design involve the selection of specific metabolic pathways to be blocked. Many proteases, enzymes involved in essential processes to the survival of the parasite, such as cruzain, are thought of as potential therapeutic targets. Cruzain, the major cysteine protease of T. cruzi, is responsible for cellular replication, survival and invasion of the host cell, being an excellent biochemical target for the drug discovery of new antichagasic agents. Starting from the knowledge of nitrofural (5-nitro-2-furaldehyde semicarbazone) as an antibacterial agent and as a known cruzain inhibitor, we used it as a template for the search of new drugs against Chagas disease. In the present work, bioisosteric modifications were used as a strategy to design new compounds as potential cruzain inhibitors. 27 sulfonilhydrazones derivatives were synthesized, had their purity assessed by HPLC and were characterized through their melting point, UV spectroscopy and NMR 1H and 13C. The synthesized compounds were evaluated against epimastigote strains of T. cruzi, showing inhibitory activity on cellular growth between 20 and 100% at 100 µM. In the cruzain enzymatic assays, the nitro derivatives showed activity around 50% of inhibition at 100 µM, and IC50 around 100 µM. By the results, we can suggest that the presence of the nitro group in some compounds should be responsible for triponocidal activity. Given the known toxicity of nitro compounds, the derivatives without the nitro goup, Ie, IIf and IIIe, may be considered promising given their intermediate inhibitory activity on cruzain, among 45% and 60% at 100 µM. The coumpound IIf also showed 23,4% inhibitory activity at 100 µM. Therefore, these compounds could be employed as starting points on the search of new effective antichagasic agents.
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Souza, Alfredo Danilo Ferreira de. "Otimização de novos inibidores da di-idrofolato redutase de Mycobaterium tuberculosis (mtDHFR): Docking molecular, síntese, avaliação da inibição enzimática e da atividade antimicobacte." Universidade de São Paulo, 2018. http://www.teses.usp.br/teses/disponiveis/9/9138/tde-28012019-115311/.
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A tuberculose (TB) é considerada uma das principais doenças infecciosas e apresenta fatores críticos como a relação com o HIV/AIDS, tratamento longo e a resistência a múltiplos fármacos. A enzima di-hidrofolato redutase das micobactérias (mtDHFR) é um alvo pouco explorado e apresenta grande potencial para o desenvolvimento de novos fármacos contra TB. Estudos preliminares obtiveram fragmentos com baixa afinidade à mtDHFR, entretanto com potencial para otimização. Com isso, o fragmento foi usado como protótipo para a proposição de 22 análogos. Os compostos foram planejados utilizando informações sobre ligantes e a estrutura tridimensional de mtDHFR, além do biososterismo como estratégia norteadora. Os ensaios de docking molecular com a mtDHFR revelaram que os análogos propostos tiveram escores interessantes e, além disso, a inserção de substituintes demonstrou favorecer a ligação à enzima, o que corroborou o planejamento. Com isso, sintetizou-se 22 análogos planejados e o protótipo MB872, por meio de protocolos de alquilação, hidrólise e cicloadição 1,3 dipolar para os compostos com anéis triazol e tetrazol. Os compostos foram obtidos com rendimentos de bom a ótimo (60 ~ 90%) e suas estruturas foram elucidadas por RMN 1H e 13C. Os resultados do ensaio de inibição enzimática corroboraram com os dados de docking, uma vez que a presença do grupo carboxílico revelou ser importante para a atividade. Além disso, alguns dos compostos revelaram atividades interessantes, entre 8 a 40 µM, sendo que o mais ativo apresentou IC50 de 7 µM. Ensaios de cinética enzimática com o análogo mais ativo indicou uma inibição não competitiva com o substrato natural da enzima, uma vez que os valores de Km se mantiveram constantes, enquanto Vmax decaiu (0,22 µM e 0,43 - 0,34 ΔFU/min, respectivamente). Os análogos sintetizados foram mandados para ensaio in vitro para avaliar a atividade frente a micobactéria.Tuberculosis (TB) is an important infectious disease and presents critical factors such as the relationship with HIV / AIDS, long treatment and resistance to multiple drugs. The enzyme dihydrofolate reductase from mycobacteria (mtDHFR) is a poorly explored and presents great potential to be a target for new drugs against TB. Preliminary studies have obtained fragments with low affinity to mtDHFR, but with potential to become lead compounds. Therefore, the fragment was used as a prototype for 22 analogues proposed in this work. The compounds were designed using bioisosterism, information about ligands and the three-dimensional structure of mtDHFR. Molecular docking assays with mtDHFR revealed satisfactory scores for anlogues. Furthermore, the insertion of substituents seemed to increase the affinity with the enzyme. Thereby, twenty two analogues and prototype were synthesized using alkylation, hydrolysiss and 1,3-dipolar cycloaddition methods. The compounds were obtained in good yields (60 ~ 90%) and their structures were elucidated with 1H and 13C NMR spectroscopy. The enzymatic affinity assay corroborates docking results, because the presence of carboxyl group showed to be important for the activity. Furthermore, some of the compounds revealead interesting activities, ranging 8 to 40 µM. The most active showed IC50 of 7 µM and enzyme kinetics assays indicated noncompetitive inhibition with natural enzyme substrate. The synthesized analogs were sent for in vitro assay to assess mycobacteria activity.
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Acquaah-Harrison, George. "Antibacterial Agents: 1,4-Disubstituted 1,2,3-Triazole Analogs of the Oxazolidinone." Ohio : Ohio University, 2010. http://www.ohiolink.edu/etd/view.cgi?ohiou1273250347.
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Rönn, Robert. "Design and Synthesis of Inhibitors Targeting the Hepatitis C Virus NS3 Protease : Focus on C-Terminal Acyl Sulfonamides." Doctoral thesis, Uppsala universitet, Institutionen för läkemedelskemi, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-7814.
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Hepatitis C is a global health problem that affects approximately 120–180 million people. This viral infection causes serious liver diseases and the therapy available suffers from low efficiency and severe side effects. Consequently, there is a huge unmet medical need for new therapeutic agents to combat the hepatitis C virus (HCV). Inhibition of the viral NS3 protease has recently emerged as a promising approach to defeat this infection, and the first HCV NS3 protease inhibitors have now entered clinical trials. In this project, several novel HCV NS3 protease inhibitors have been designed, synthesized and biochemically evaluated. Inhibitors with various P1 C-terminal functional groups intended as potential bioisosteres to the carboxylic acid found in product-based inhibitors have been revealed. Special focus has been placed on establishing structure–activity relationships of inhibitors containing the promising P1 C-terminal acyl sulfonamide group. The properties of the acyl sulfonamide functionality that are important for producing potent inhibitors have been identified. In addition, the advantages of the acyl sulfonamide group compared to the carboxylic acid have been demonstrated in both enzymatic and cell-based assays. Besides the acyl sulfonamide functionality, the acyl cyanamide and the acyl sulfinamide groups have been identified as new carboxylic acid bioisosteres in HCV NS3 protease inhibitors. The synthetic work included the development of a fast and convenient methodology for the preparation of aryl acyl sulfonamides. The use of microwave heating and Mo(CO)6 as a solid carbon monoxide source provided aryl acyl sulfonamides from aryl halides in excellent yields. This method was subsequently used in the decoration of novel HCV NS3 protease inhibitors comprising a non-natural P1 moiety. This new class of compounds can be used as lead structures in a future optimization process aimed at producing more drug-like HCV NS3 protease inhibitors.
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Bigatão, Hamilton Marcel. "Antichagásicos potenciais: planejamento e estudo da síntese de biosósteros imidazólicos e triazólicos do hidroximetilnitrofural." Universidade de São Paulo, 2011. http://www.teses.usp.br/teses/disponiveis/9/9138/tde-31012011-154537/.
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A doença de Chagas é uma doença negligenciada, endêmica, causada pelo protozoário Trypanosoma cruzi, parasita intracelular obrigatório, que necessita de seres vivos de duas classes totalmente diferentes (insetos, o mais comum, Triatoma infestans, e mamíferos, como, por exemplo, o homem) para completar seu ciclo. Em 2009, a doença completou 100 anos de conhecimento pela humanidade, no entanto não há motivos para comemoração, uma vez que, apesar de quase totalmente descrita desde sua descoberta por Carlos Chagas, não há um fármaco que seja ativo na fase crônica. Sabendo que a fase aguda é de difícil diagnóstico e devido à ausência de sintomas indicativos, pode-se dizer que a doença de Chagas é praticamente incurável. Os fármacos utilizados na terapêutica, benznidazol e nifurtimox, são os mesmos há várias décadas. É, portanto, imperioso se buscar candidatos a fármacos antichagásicos que possam suprir o arsenal terapêutico altamente escasso da parasitose. O hidroximetilnitrofural (NFOH), derivado sintetizado em nosso laboratório, se mostrou antichagásico promissor, com maior atividade in vitro em relação ao benznidazol, além de ser quatro vezes menos tóxico que o nitrofural, seu precursor. Por outro lado, o bioisosterismo consiste na substituição de elementos ou grupos a fim de se obter melhores propriedades biológicas do fármaco protótipo, caracterizando-se, assim, como forma de modificação molecular. Assim sendo, o objetivo do presente trabalho foi a aplicação de bioisosterismo no anel furânico do NFOH, sintetizando derivados imidazólicos e triazólicos, além do mesmo tipo de modificação molecular na cadeia lateral, através da formação de semicarbazonas e tiossemicarbazonas. Dessa forma, pretendeu-se sintetizar compostos que atuariam sobre o parasita por três diferentes vias: a geração de peróxido de hidrogênio, tóxico por ser dificilmente reduzido pelo parasita, através de reações de oxidorredução mediadas pelo grupo nitro; a inibição da enzima cruzaína (presente somente no Trypanosoma cruzi) e inibição da14-α esterol desmetilase, enzima fundamental na cascata de reações de formação de ergosterol, componente da parede celular do parasita. A síntese dos imidazóis, prevista para ser realizada em cinco ou seis etapas (há possibilidade de realizar em dez etapas através de outra rota), teve duas etapas completadas, com a proteção, utilizando tritila, do nitrogênio 1 do 4-carboxialdeído imidazol e a produção do agente nitrante. Houve problemas na proteção do hidrogênio ligado à carbonila do mesmo composto, necessária para o êxito da nitração ao carbono 2, seguida de reação de acoplamento com a semicarbazona (e tiossemicarbazona) e hidroximetilação. No caso da síntese dos triazóis, também prevista para ser realizada em cinco etapas, concluíram-se duas delas - oxidação do grupo amina a nitro do 3-aminotriazol e hidroximetilação no nitrogênio 1, utilizando formaldeído. A etapa seguinte, de oxidação e formação da carbonila, a fim de permitir reação com semicarbazona, não foi bem-sucedida, uma vez que o composto não se mostrou estável nas condições da reação. Tentativas com diferentes métodos foram realizadas, mas não houve sucesso na formação da carbonila ligada ao nitrogênio 1. Análogos do nitrofural contendo anéis nitrobenzênicos e imidazólicos (sem nitro) foram sintetizados e poderão ser ensaiados no prosseguimento deste trabalho. Através de Modelagem Molecular, realizou-se avaliação comparativa entre a capacidade de redução do grupo nitro dos quatro compostos propostos no projeto em relação aos análogos já sintetizados e conhecidos (contendo anel furânico e tiofênico), além de outros catorze compostos propostos contendo mudanças no anel aromático e na semicarbazona/tiossemicarbazona. Foi possível prever a atividade por um dos mecanismos propostos, que podem estar envolvidos também com toxicidade. Dentre os 22 derivados, o composto imidazólico contendo semicarbazona, que está sendo sintetizado, mostrou-se com maior capacidade de sofrer redução no grupo nitro. Dinâmica molecular associada ao docking foi utilizada como ferramenta a fim de se avaliar o mecanismo de inibição sobre a cruzaína. Assim, selecionaram-se o NFOH, além de outros sete bioisósteros, dentre eles os quatro que foram propostos neste projeto. Após dinâmica molecular de 3 ns, observou-se que a CYS25 da proteína se distanciou da carbonila do NFOH, sugerindo dificuldade ao ataque proposto na literatura para outros compostos contendo esta região da molécula. Estudos adicionais sobre a forma de inibição do NFOH à cruzaína se fazem necessários.Chagas\' disease is an endemic, neglected disease caused by Trypanosoma cruzi protozoan, which is an intracellular parasite that requires another type of completely different species (insects, the most common, Triatoma infestans and mammals as human being, for example) to complete its cycle. In 2009, this sickness completed 100 years of discovery, however there is no reason for a happy celebration. In spite of being completely described by Carlos Chagas since that time, there is not even one drug that is active in the chronic phase. As the acute phase is very hard to diagnose, and due to the absence of symptoms, nowadays Chagas\' disease is practically incurable. The drugs used in the therapeutics are the same since decades ago, benznidazole and nifurtimox. So, it is peremptory to find new candidates of antichagasic drugs that may supply the scarce of therapeutic options to this parasitosis. Hydroxymethylnitrofurazone (NFOH), which is already synthesized in our laboratory, has shown to be promising antichagasic with higher activity and four times less toxic in vitro when compared to benznidazole, its precursor. On the other hand, bioisosterism is a useful kind of molecular modification that consists of substitution of elements and groups in order to obtain better biological properties of a prototype. Therefore, the aim of this work was the application of bioisosterism in the furan ring of NFOH by synthesizing imidazole and triazole aromatic ring compounds. Bioisosterism is also applied in the side chain, while semicarbazone and thiosemicarbazone compounds were designed for these possessing nitrogen aromatic rings. So, it was attempted to synthesize compounds that are able to kill the parasite by three different ways: generation of hydrogen peroxide by nitro group, which is highly toxic to the parasite that have problems to neutralize it; inhibition of cruzain, a major cysteine-protease that is present in some catalytic ways of the parasite, and inhibition of 14-α sterol demethylase, a fundamental enzyme in the pathway of ergosterol production, which is a cell wall component. In the imidazole synthesis route, two of the five or six steps (there is possibility to achieve in ten steps, by another route), planned were completed, with the trityl protection of the nitrogen 1 of 4-carboxaldehyde imidazole and the nitrating agent was also produced successfully. Some problems were observed in the protection of the hydrogen bound to the same compound carbonyl by ketal production, which is necessary to provide the nitration in the carbon 2, followed by coupling reaction to the semicarbazide or thiosemicarbazide and the hydroxymethylation, which is the last step of synthesis. In the triazole synthesis, which was predicted to be achieved in five steps, only two were also concluded oxidation of the amino group to produce 3-nitrotriazole and hydroxymethilation of the nitrogen 1, using formaldehyde. The next step, oxidation to produce carbonyl, in order to allow reaction with the thio or semicarbazone moiety, was not well succeeded, because this compound was not stable in the reaction conditions. Different methods were tempted, but no success was observed for the carbonyl formation on the nitrogen 1. Nitrofurazone (NF) analogs containing nitrobenzenic and imidazolic nucleus (without nitro presence) were synthesized and now are able to be tested in a possible continuation of this work. By using molecular modeling, a comparative evaluation of the nitro reduction capacity by the nitrocompounds designed in this project related with other bioisosters that were already synthesized by our group have been made, in addition to other selected bioisosters. It was possible to predict the activity of these compounds by one of the proposed mechanisms, which can also be evolved with toxicity. Among the 22 calculated compounds, the imidazole compound with sulfur in the side chain presented higher ability to nitro reduction. Molecular dynamics, associated with docking, was used as a tool in order to evaluate the inhibition mechanism over the cruzain. So, NFOH and seven other bioisosters were chosen. After 3 ns of simulation, it was observed that the CYS 25 residue of the protein was distant to the NFOH carbonyl, suggesting difficulty in the proposed in the literature interaction for other compounds containing the moiety. Additional studies to clarify the inhibition form of NFOH to cruzain are necessary.
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Galo, Oswaldo Aparecido. "Síntese de análogos de benznidazol por \"click chemistry\" e avaliação de atividade antiparasitária." Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/60/60138/tde-22022013-155336/.
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A tripanossomíase sul-americana, também conhecida como Doença de Chagas é uma enfermidade endêmica da América Latina.A doença é causada pelo protozoário Trypanosoma cruzi, cuja transmissão em seres humanos e outros mamíferos ocorrem, principalmente, através das fezes do inseto \"barbeiro\" (triatoma infestans) infectado.Desde a descoberta já foram realizadas inúmeras tentativas de tratamento sem obter quimioterapia eficaz. Hoje o tratamento é realizado pelo uso do fármaco nitroheterocíclico benznidazol. Porém esse composto só é utilizado na fase aguda da doença e tem sua eficácia variada de acordo com a área geográfica, provavelmente como consequência de variação de cepas do parasita e apresenta graves efeitos colaterais. Uma ferramenta interessante em Química Medicinal é o uso do bioisosterismo para a síntese de moléculas análogas, que por possuírem propriedades biológicas relacionáveis geralmente atuam no mesmo alvo farmacológico como agonistas ou antagonistas. Por outro lado, as reações relacionadas às condensações de cicloadição 1,3 dipolar catalisadas por Cu(I), envolvendo estratégias de \"click chemistry\" tem como pontos positivos o fato de geralmente não formarem subprodutos, serem de fácil execução e apresentarem rendimentos elevados. Partindo de dois compostos comerciais (benzilamina e cloreto de cloro acetila) efetuou-se a síntese de uma biblioteca de vinte e três compostos análogos ao benznidazol através de uma rota sintética curta e de fácil execução. Foram realizados ensaios de atividade tripanocida envolvendo a cepa Tulahuen de T.cruzi, bem como ensaios de citotoxicidade.The South American trypanosomiasis, also known as Chagas\' disease is an endemic disease in Latin America. The disease is caused by the protozoan Trypanosoma cruzi, whose transmission in humans and other mammals occur primarily through the faeces of the insect \"barbeiro\" (triatoma infestans) infection. Since the discovery already been carried out many attempts to obtain effective chemotherapy treatment. Today\'s treatment is accomplished through the use of the drug nitro-heterocyclic benznidazole. However this compound is only used in the acute phase of the disease and its effectiveness is varied in accordance with the geographical area, probably as a consequence of the variation of strains of the parasite and presents serious side effects. An interesting tool in medicinal chemistry is the use of bioisosterism for the synthesis of analogous molecules, which possess biological properties relatable generally act on the same target as pharmacological agonists or antagonists. Moreover, the reactions related to condensations of 1.3 dipolar cycloaddition catalyzed by Cu(I), involving strategies \"click chemistry\" has the strengths of the fact usually do not form byproducts, being easy to perform and present high yields. Starting from two commercial compounds benzylamine and chloro acetyl chloride) we performed the synthesis of a library of twenty-three analog compounds to benznidazole via a synthetic route short and easy to perform. Tests of trypanocidal activity involving Tulahuen strain of T. cruzi, and cytotoxicity assays.
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Wångsell, Fredrik. "Design and Synthesis of Aspartic and Serine Protease Inhibitors : Targeting the BACE-1 and the HCV NS3 Protease." Doctoral thesis, Uppsala universitet, Institutionen för läkemedelskemi, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-108985.
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This thesis describes work done to design and synthesize protease inhibitors, with the intention of developing therapeutic agents for Alzheimer’s disease (AD) and the chronic liver condition caused by infection of the hepatitis C virus (HCV). AD is the most common form of dementia, and HCV infection is the primary reason for liver transplantation in industrialized countries. Today, these two illnesses affect 24 and 170 million people, respectively. It has been shown that the human aspartic protease BACE-1 plays an important role in the development of AD, and thus inhibition of BACE-1 may offer a way to improve the quality of life of individuals afflicted with the disease. Furthermore, it is known that the serine protease NS3 is a vital component in the replication of HCV. Several novel potent BACE-1 inhibitors encompassing different transition state mimics were prepared. First, a hydroxyethylene moiety encompassing a secondary hydroxyl group was evaluated as a transition state analogue, producing inhibitors in the low nanomolar range. Various tertiary hydroxyl isosteres were also investigated as the central core, with the aim of shielding the pivotal hydroxyl group. These transition state isosteres consisted of tertiary hydroxyl analogues of previously used secondary hydroxyl containing norstatine, statine, and hydroxyethylamine isosteres. Several tertiary hydroxyl-containing inhibitors were found to be active in the low micromolar range. In addition, two inhibitors were co-crystallized with the BACE-1 enzyme to provide X-ray crystal structures, which furnished valuable binding information for further design of improved BACE-1 inhibitors. The goal in the HCV NS3 protease inhibitor project was to design, synthesize and evaluate a novel hydroxycyclopentene bioisostere to the previously used acyl-hydroxyproline moiety. The investigation revealed that it was possible to synthesize inhibitors containing this new bioisostere that were potent in the low nanomolar range. Further optimization by rigidification of the most active inhibitor resulted in equipotent macrocyclic compounds.
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Boëdec, Angélique. "Synthèse et évaluation biologique d'analogues du phosphoantigène (E)-1-hydroxy-2-méthylbut-2-ényl diphosphate modulant l’activité des lymphocytes T Vγ9Vδ2." Thesis, Aix-Marseille 2, 2011. http://www.theses.fr/2011AIX22080.
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Les lymphocytes T Vγ9Vδ2 ont été étudiées depuis les années quatre-vingt pour leurs puissantes propriétés anti-infectieuses, démontrées aussi bien in vitro que dans des modèles animaux et confirmées par de nombreuses observations cliniques.L'implication de ces cellules dans l’immunité anti-infectieuse réside dans leur reconnaissance d’une famille de molécules produites par des pathogènes intracellulaires appelées phosphoantigènes dont l’activateur naturel le plus puissant à ce jour est le HDMAPP : (E)-1-hydroxy-2-méthylbut-2-ényl 4-diphosphate.Après avoir défini et synthétisé un synthon clé, sur lequel nous avons couplé des groupements pyrophosphonate et pyrophosphoramidate, nous avons réalisé des bioisostères de la molécule HDMAPP. Nous avons également synthétisé des isomères géométriques, analogue de position et isomères cis, des dérivés carbonylés, acide et ester. La bioactivité de ces molécules a été testée in vitro et pour les plus actives in vivo. Les résultats obtenus indiquent que l'utilisation de composés bioisostères de HDMAPP peuvent représenter de nouvelles pistes prometteuses pour l'immunothérapieVγ9Vδ2 T lymphocytes have been studied since the early eighties for their potent anti-infectious properties, attested both in vitro and in animal models and supported by many clinical observations. The involvement of Vγ9Vδ2 T cells in anti-infectious immunity lies in their recognition of an original family of molecules produced by intracellular pathogens so-called phosphoantigens and whose most potent natural activator to date is the HDMAPP: (E)-1-hydroxy-2-methylbut -2-enyl diphosphate.Having defined and synthesized a key intermediate on which we have linked pyrophosphonate and pyrophosphoramidate moieties, we have made bioisosters of the molecule HDMAPP. We also synthesized geometric isomers, analogue of position and cis isomers, carbonyl derivatives, acid and ester. The bioactivity of these molecules was tested in vitro and for the most active in vivo. The results indicate that the use of bioisosters compounds of HDMAPP may represent promising new leads for immunotherapy
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Silva, Fábio Pedrosa Lins. "Síntese de novos adutos de Morita-Baylis-Hillman: bioisosterismo clássico na otimização de leishmanicidas." Universidade Federal da Paraíba, 2009. http://tede.biblioteca.ufpb.br:8080/handle/tede/7101.
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Previous issue date: 2009-11-27Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES
This work was designed using the concept of classical bioisosterism where isoelectronic OH groups were replaced by the CH3 group, aimed at finding a relationship between the lipossolubility of the adducts Morita-Baylis-Hillman (AMBH) and its biological activity. Was developed in this work, synthetic methodologies for the preparation of 16 AMBH unprecedented (47-62), getting good and high yields. Initially was synthesized AMBH 8 using the 2-hydroxyethyl Acrylate 45 as Michael acceptor, giving the adducts 47 (2-hydroxyethyl [2-(hydroxy( 2-nitrophenyl)methyl)] acrylate, 71%), 48 (2-hydroxyethyl [2-(hydroxy( 3-nitrophenyl)methyl)] acrylate, 50%), 49 (2-hydroxyethyl [2-(hydroxy(4- nitrophenyl)methyl)] acrylate, 62%), 50 (2-hydroxyethyl [2-(hydroxy(pyridin-2- yl)methyl)] acrylate, 94%), 51 (2-hydroxyethyl [2-(hydroxy(pyridin-3-yl) methyl)] acrylate, 83%), 52 (2-hydroxyethyl [2-(hydroxy(pyridin-4-yl)methyl)] acrylate, 80%), 53 (2-hydroxyethyl [2-((4-bromophenyl)(hydroxy)methyl)] acrylate, 67%), 54 (2-hydroxyethyl [2-(hydroxy(naphthalen-2-yl)methyl)] acrylate, 71%). The second step of the synthesis was the preparation of Propyl Acrylate (46), from acrylic acid and propanol (yield 98%), which was later used as Michael acceptors in the synthesis of AMBH 55 (Propyl [2-(hydroxy(2-nitrophenyl) methyl)] acrylate, 68%), 56 (Propyl [2-(hydroxy(3-nitrophenyl)methyl)] acrylate, 73%), 57 (Propyl [2-(hydroxy(4-nitrophenyl)methyl)] acrylate, 97%), 58 (Propyl [2-(hydroxy(pyridin-2-yl)methyl)]acrylate, 70%), 59 (Propyl [2- (hydroxy(pyridin-3-yl)methyl)acrylate], 80%), 60 (Propyl [2-(hydroxy(pyridin-4- yl)methyl)] acrylate, 66%), 61 (Propyl [2-((4-bromophenyl)(hydroxy)methyl)] acrylate, 64%), 62 (Propyl [2-(hydroxy(naphthalen-2-yl)methyl)] acrylate, 60%). All of these adducts were bioavailiated in vitro against the parasite Leishmania amazonensis, their cytotoxicity in macrophages were studied and their therapeutic indices calculated. Unlike expected, the bioisosteric modification not presented a direct relationship between the lipossolubility (Log P) of these compounds and their biological activity. All adducts showed strong activity antipromastigote, being the compounds 47, 55, 49, 57, 53, 54 and 62 the most actives in L. amazonensis, all with IC50 less than 60μM. Among them the AMBH 47 was the most active and that presented the higher therapeutic index, which is the prototype substance of this work.
Este trabalho foi idealizado utilizando o conceito de bioisosterismo clássico, onde grupos isoeletrônicos OH foram substituídos pelo grupo CH3, visando encontrar uma relação entre a lipossolubilidade dos Adutos de Morita-Baylis- Hillman (AMBH) e sua atividade biológica. Foram desenvolvidos neste trabalho, metodologias sintéticas para a preparação de 16 AMBH inéditos (47-62), em bons a altos rendimentos. Inicialmente foi sintetizado 8 AMBH utilizando o Acrilato de 2-hidroxietila (45) como aceptor de Michael, obtendo os adutos 47(Acrilato de [2-(hidroxi(2-nitrofenil)metil)] de 2-hidroxietila, 71%), 48 (Acrilato de [2-(hidroxi(3-nitrofenil)metil)] de 2-hidroxietila, 50%), 49 (Acrilato de [2-(hidroxi(4-nitrofenil)metil)] de 2-hidroxietila, 62%), 50 (Acrilato de [2-(hidroxi( piridin-2-il)metil)] de 2-hidroxietila, 94%), 51(Acrilato de [2-(hidroxi(piridin- 3-il)metil)] de 2-hidroxietila, 83%), 52 (Acrilato de [2-(hidroxi(piridin-4-il)metil)] de 2-hidroxietila, 80%), 53 (Acrilato de [2-((4-bromofenil)(hidroxi)metil)] de 2- hidroxietila, 67%), 54 (Acrilato de [2-(hidroxi(naftalen-2-il)metil) de 2-hidroxietila, 71%). A segunda etapa de síntese foi a preparação do Acrilato de propila (46), a partir do ácido acrílico e do propanol (rendimento de 98%), que posteriormente foi utilizado como aceptor de Micheal na síntese dos AMBH 55(Acrilato de [2-(hidroxi-(2-nitrofenil)metil)] de propila, 68%), 56 (Acrilato de [2-(hidroxi-(3-nitrofenil)metil)] de propila 73%), 57 (Acrilato de [2-(hidroxi-(4- nitrofenil)metil)] de propila, 97%), 58 (Acrilato de [2-(hidroxi-(piridin-2- il)metil)] de propila, 70%), 59 (Acrilato de [2-(hidroxi-(piridin-3-il)metil)] de propila, 80%), 60 (Acrilato de [2-(hidroxi-(piridin-4-il)metil)] de propila, 66%), 61(Acrilato de [2-((4-bromofenil)(hidroxi)metil)] de propila, 64%), 62 (Acrilato de [2-(hidroxi(nafthalen-2-il)metil)] de propila, 60%). Todos estes adutos foram bioavaliados in vitro contra o parasita Leishmania amazonensis, suas citotoxicidades em macrófagos foram estudadas e seus índices terapêuticos calculados. Diferentemente do esperado, a modificação bioisostérica não apresentou uma relação direta entre a lipossolubilidade (Log P) destes compostos e a sua atividade biológica. Todos os adutos apresentaram forte atividade antipromastigota, sendo os compostos 47, 55, 49, 57, 53, 54 e 62 os mais ativos em L. amazonensis, todos com IC50 menores que 60QM. Entre eles o AMBH 47 foi o mais ativo e o que apresentou o maior índice terapêutico, sendo este a substância protótipo deste trabalho.
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Šramel, Peter. "A synthesis and biological screening of predicted inhibitors of Tyrosine Kinases, e.g. KDR, designed in silico." Thesis, Strasbourg, 2017. http://www.theses.fr/2017STRAF064.
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Les protéines kinases représentent le groupe d'enzymes qui servent d'intermédiaire pour la phosphorylation de protéines - le transfert d'un groupe phosphate de l'adénosine triphosphate(ATP) sur des chaînes latérales correspondantes de tyrosine, de serine ou de thréonine des acides aminées. La phosphorylation de protéines est un des outils les plus importants pour la régulation de l'activité cellulaire. La « signalisation » cellulaire par le récepteur de tyrosine kinase VEGFR2 (KDR) appartient aux réactions biochimiques clés influençant la croissance de tumeurs. L'inhibition thérapeutique de cette réaction à l'aide des composés de faible poids moléculaire spécifiques est devenue une stratégie utile dans le cadre des thérapies anticancéreuses. Ce travail a amené à la découverte de 16 substances biologiquement actives sur la base N,5-diaryloxazol-2-amine (IC50, VEGFR2 TK). D'excellents résultats ont été atteints notamment dans le cas des substances 189, 191, 211, 214, 220, 221, 223 et 4 qui montrent une activité inhibitrice inférieure à 500 nMProtein kinases represent a group of enzymes responsible for phosphorylation - transfer of aphosphate group from adenosine triphosphate (ATP) to tyrosine or serine/threonine residues. Protein phosphorylation is one of the most important tools regulating a cell activity. A cell "signalization" through an endothelial receptor tyrosine kinase VEGFR2 TK (KDR) is the important pathway influencing growth of a tumor. Small-molecule inhibitors of VEGFR2 TK (VEGFR2 TKls) have become an important tool for the treatment of various types of cancer. This dissertation thesis resulted in a discovery of 16 biologically active N,5-diaryloxazol-2-amines (IC50, VEGFR2 TK). Very good results were achieved especially with compounds 189, 191, 211, 214, 220, 221, 223 and 4 exhibiting the activity under 500 nM
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Mello, Rodrigo Brito de. "Produção de biblioteca de compostos derivados de produtos naturais: síntese e estudo de atividades biológicas." Universidade de São Paulo, 2014. http://www.teses.usp.br/teses/disponiveis/60/60138/tde-17042015-151409/.
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O presente trabalho trata da semissíntese de análogos de importantes compostos líderes (afidicolina, lausona, lapachol e CAPE) utilizando técnicas de química medicinal como bioisosterismo, adição de grupamento funcional e simplificação molecular. Dessa forma foi possível obter uma biblioteca de análogos racionais, visando a manipulação de parâmetros físico-químicos e estruturais, para fins de bioprospecção. Foram desenvolvidos derivados de afidicolina mais lipofílicos, por meio da acilação das hidroxilas presentes na estrutura química deste terpeno. Tentativas de formação de bioisósteros, sais e de ésteres fosfato das hidroxinaftoquinonas naturais - lapachol e lausona, foram realizadas visando avaliar a influência do pKa sobre a atividade deste tipo de moléculas, bem como aumentar hidrossolubilidade. Neste caso, foram observadas reações paralelas, como um rearranjo molecular para a formação de aminonaftoquinonas, no estudo da cicloadição de azida de sódio com grupos cianos. Ademais, foi estudado o efeito da simplificação molecular de CAPE (fenetil éster do ácido cafeico), visando entender os requisitos estruturais de atividade antitumoral desta classe de compostos. Neste trabalho, foram obtidas 14 moléculas e testadas para diferentes atividades biológicas. Derivados naftoquinoidais se mostraram ativos frente à inibição de DHODH em ensaio sobre a enzima e também em ensaio celular. Adicionalmente, análogos simplificados do CAPE apresentaram alta atividade antitumoral, com segurança, em comparação ao controle 5-fluorouracila.The present study aimed the semi-synthesis of analogues from important lead compounds (aphidicolin, lausone, lapachol and CAPE) by using medicinal chemistry strategies, such as bioisosterism, addition of functional groups and molecular simplification. Thus, we obtained a library of rational analogues, aiming the manipulation of physicochemical and structural parameters with bioprospecting purposes. We developed more lipophilic aphidicolin derivatives by acylation of the hydroxyl groups present in the structure of this terpene. Attempts towards the development of phosphate salts bioisosters from the hydroxinaftoquinones lapachol and lausone in order to evaluate the influence the pKa in the biological activity of these class compounds as well as to increase the water solubility. In this last case, we observed parallel reactions, as a molecular rearrangement for the formation of the aminonaftoquinones during the study of cycloaddition with cyanides and azides. In addition, we studied the effects of molecular simplification of CAPE (caffeic acid phenethyl ester), to better understand the structural requirements for antitumoral activity of this class of compounds. In the present work we obtained 14 molecules which were also tested for different biological activities. Naftoquinoidais derivatives showed inhibition activity on enzymatic essay on DHODH and on cellular essay. Moreover, simplified molecules from CAPE showed high antitumoral activity and safety in comparison to the control 5- fluorouracil.
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Metayer, Benoît. "Activation acide ou superacide : synthèse de nouveaux composés azotés fluorés et polycycliques." Thesis, Poitiers, 2014. http://www.theses.fr/2014POIT2291/document.
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Le fluor est devenu un élément incontournable en chimie médicinale. Les propriétés physico-chimiques induites par l'incorporation de cet atome dans les composés organiques en font un outil efficace dans la conception de mimes de fonctions chimiques. Les difficultés pour accéder aux composés azotés fluorés permettent d'envisager l'utilisation des milieux superacides et acides fluorants comme alternative de synthèse.Dans la première partie, la réactivité de N-allyl-N-arylbenzènesulfonamides en milieu superacide HF / SbF5 a été étudiée. La non observation de la cyclisation de type Friedel-Craft intramoléculaire initialement envisagée pour ces composés a été expliquée grâce à une étude mécanistique utilisant la RMN basse température in situ. En modifiant les conditions opératoires, la synthèse de N-arylbenzènesulfonamides α-fluorés a pu être développée. Les structures obtenues ont été testées pour l'inhibition des anhydrases carboniques.Dans la seconde partie, une nouvelle réaction d'hydrofluoration d'ynamides dans le milieu HF / pyridine a été développée. Cette stratégie a permis d'obtenir régio- et stéréosélectivement des (E)-α-fluoroènamides originaux. Par analogie avec les fluoroalcènes décrits en tant que mimes d'amides, les α-fluoroènamides sont potentiellement des isostères de la fonction urée. Le biomimétisme de ces structures est discuté grâce aux résultats d'études structurales réalisées par modélisation moléculaire. La réactivité surprenante de structures ortho-substituées en milieu superacide a permis le développement d'une réaction de polycyclisation intramoléculaire d'ynamides, cette nouvelle méthode permettant d'accéder en une étape à des polycycles azotés à haute valeur ajoutéeDuring the last decades, fluorine became an essential element in medicinal chemistry. The original physical and chemical properties induced by the incorporation of this atom in organic compounds led to the development of fluorinated compounds as bioisosters in medicinal chemistry. Difficulties to access to fluorinated nitrogen containing compounds by "classical methods" led to the use of superacid as an alternative for their synthesis.In the first part of this work, the reactivity of unsaturated N-arylbenzenesulfonamides in superacidic media HF / SbF5 was studied. Intramolecular cyclisation of Friedel-Craft type expected for these compounds was studied and explored through a mechanistic study based on in situ low temperature NMR experiments. By modifying the operating conditions, the synthesis of α-fluorinated N-arylbenzenesulfonamide compounds was developed. The synthetized structures were then tested for carbonic anhydrase inhibition.In a second part, a new hydrofluorination reaction of ynamides was developed, using fluorhydric acid / pyridine media. This strategy allowed to access regio- and stereoselectively to original (E)-α-fluoroenamides. By analogy with the described fluoroalkenes as peptid bond isosters, α-fluoroenamides could potentially be considered as urea bioisosters. The bioisosterism of these structures was discussed and evaluated by using molecular modelling. The surprising reactivity of ortho-substitued structures in superacid media allowed the development of an intramolecular polycyclisation reaction, offering a one step route to complex nitrogen containing molecular polycyclic motif
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Santos, Paulo Pitasse. "Planejamento, S?ntese e Avalia??o de Derivados 1,2,4-Oxadiaz?licos com Potencial Atividade Tripanocida." Universidade Federal Rural do Rio de Janeiro, 2017. https://tede.ufrrj.br/jspui/handle/jspui/2019.
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Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico - CNPq
Chagas disease was studied and described by the Brazilian sanitarist and physician Carlos Chagas in 1909. It is caused by the protozoan Trypanosoma cruzi and presents complex clinical manifestations. However, since its discovery, little progress has been made in the chemotherapeutic treatment of Chagas' disease. The only available drug for its treatment (benzonidazole) is not completely efficient and is associated with the development of several side effects. From the knowledge of the antiparasitic activity of the natural amidic alkaloid piperine, this work focused on the proposition of new structurally-similar molecules with trypanocidal potential. From the principles of bioisosterism, a series of new 1,2,4-oxadiazoles were proposed. Its synthesis was designed from the corresponding 3-arylacrylic acids to give the respective acyl chlorides by reaction with oxalyl chloride. The subsequent step involves O-acylation of the properly substituted benzamidoxime following the cyclization reaction of the oxadiazolic ring, which occurs in solid support (silica gel) using microwave irradiation. The characterization of the products was done by determination of melting points, 1H and 13C NMR, infrared espectrometry and high and low resolution mass spectrometry. The present work also presents information about the biological activity profile of the molecules synthesized against epimastigote forms of the T. cruzi protozoan and against primary mammalian cells, allowing the calculation of their selectivity indexes. Investigations about the possible mechanisms of action of the derivatives on T. cruzi indicate that there are no influences on the enzymatic action of the protease cruazain, on the cell cycle of the parasite or on the biosynthesis of membrane sterols catalyzed by the enzyme CYP51. The developed sinthetic methodology can be applied in the expansion of the series of analogues derivatives. The perspectives of this work also include the biological evaluation against amastigote and trypomastigote forms of the parasite.
A doen?a de Chagas foi estudada e descrita pelo m?dico sanitarista e cientista brasileiro Carlos Chagas, em 1909. ? causada pelo protozo?rio Trypanossoma cruzi, apresentando manifesta??es cl?nicas complexas. No entanto, desde sua descoberta, pouco se avan?ou no tratamento quimioter?pico da doen?a de Chagas, sendo o f?rmaco dispon?vel (benzonidazol) pouco eficiente e associado ? manifesta??o de diversos efeitos colaterais. A partir do conhecimento da atividade antiparasit?ria da amida natural piperina, este trabalho focou-se na proposi??o de novas mol?culas estruturalmente semelhantes com potencial tripanocida. A partir dos princ?pios do bioisosterismo, foi proposta uma s?rie de novos 1,2,4-oxadiaz?is diferentemente substitu?dos. Sua s?ntese foi concebida partir dos ?cidos 3-arilacr?licos correspondentes, obtendo-se os respectivos cloretos de acila, atrav?s da rea??o com cloreto de oxalila. A etapa posterior envolve a O-acila??o da benzamidoxima adequadamente substitu?da, seguida do fechamento do anel oxadiaz?lico, que se d? em em suporte s?lido (s?lica-gel) empregando-se irradia??o de micro-ondas. A caracteriza??o dos produtos foi feita atrav?s de ponto de fus?o, RMN 1H e 13C, espectrometria no infravermelho e espectrometria de massas de alta e baixa resolu??o. O presente trabalho ainda traz informa??es quanto ao perfil de atividade biol?gica das mol?culas sintetizadas frente a formas epimastigotas do protozo?rio Trypanosoma cruzi e frente a c?lulas prim?rias de mam?feros, permitindo que se calculasse o seu ?ndice de seletividade. Investiga??es quanto a poss?veis mecanismos de a??o dos derivados sobre o T. cruzi indicam n?o haver influ?ncias sobre a a??o enzim?tica da protease cruza?na, sobre o ciclo celular do parasito, nem sobre a bioss?ntese de ester?is de membrana, catalisada pela enzima CYP51. A metodologia qu?mica desenvolvida poder? ser aplicada na s?ntese de outros an?logos. As perspectivas deste trabalho incluem ainda a avalia??o biol?gica frente a formas amastigota e tripomastigota do parasito
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Silva, Fredson Torres. "Antichagásicos potenciais: planejamento e síntese de bioisósteros 1,2,4-triazólicos do hidroximetilnitrofural e análogos." Universidade de São Paulo, 2014. http://www.teses.usp.br/teses/disponiveis/9/9138/tde-26052015-160701/.
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A doença de Chagas, parasitose causada pelo Trypanosoma cruzi, é doença prevalente na América Latina. Estima-se que cerca de 10 milhões de pessoas estão sob o risco de infecção e, em 2008, registraram-se mais de 10 mil óbitos devido à doença. Os únicos dois fármacos disponíveis na terapêutica, nifurtimox e benznidazol, são mais eficazes no tratamento da doença no início da fase aguda. Entretanto, a fase crônica da doença não possui tratamento. O nitrofural (NF), fármaco antimicrobiano, destaca-se por possuir atividade contra o T. cruzi, porém, apresenta toxicidade. Seu derivado hidroximetilado, o hidroximetilnitrofural (NFOH), por sua vez, mostrou maior atividade antichagásica e menor toxicidade. Ante a necessidade de novos fármacos antichagásicos, a existência de alvos terapêuticos promissores como a 14α-esterol desmetilase (CYP51) e a cruzaína e mediante utilização do bioisosterismo como ferramenta de modificação molecular, realizou-se a triagem virtual de 144 ligantes análogos do NFOH pelo método de docking com o programa GOLD para a CYP51 de T. cruzi. Adicionalmente, realizou-se estudo qualitativo dos campos de interação moleculares (MIFs) com o programa GRID para a enzima humana e do parasita, homólogas entre si, estudo que revelou 9 resíduos de aminoácidos no sítio ativo da enzima parasitária que podem ser explorados no planejamento de inibidores seletivos. Neste trabalho, obtiveram-se 5 compostos inéditos, caracterizados por determinação da faixa de fusão, análise elementar, técnicas de espectroscopia no infravermelho, espectroscopia de ressonância magnética nuclear de 1H,13C, HSQC, HMBC, HETCOR e NOESY, e a atribuição dos sinais foi realizada com o auxílio de técnicas de modelagem molecular. Testaram-se 4 compostos contra a forma amastigota de T. cruzi em células da linhagem U2OS. Todos os compostos apresentaram atividade da ordem de micromolar e índices de seletividade satisfatórios. O composto LAPEN-2901 teve sua estrutura elucidada por cristalografia de raios X, apresentou toxicidade duas vezes menor que o NFOH e potência semelhante à do composto de referência benznidazol, porém menor eficácia. Os resultados obtidos ressaltam a importância de grupos nitro, 1,2,4-triazólicos e tiossemicarbazônicos para o planejamento de derivados eficazes no tratamento da fase crônica da doença de Chagas.Chagas disease, parasitosis caused by Trypanosoma cruzi, is a disease that predominates in Latin America. It is estimated that 10 million people are under the risk of infection and, in 2008, more than 10 thousand deaths were registered. The only two drugs available in the therapeutics, nifurtimox and benznidazole, showed to be more effective in the acute phase of the disease. However, there is no choice for the chronic phase. Nitrofurazone (NF), an antimicrobial drug, has activity against T. cruzi, although being toxic. Its hydroxymethyl derivative, the hydroxymethylnitrofurazone (NFOH), showed to be more active and less toxic than the prototype. Considering the need for new antichagasic drugs, the existence of promising new therapeutic targets, as 14α-esterol demethylase and cruzain, and by employing the bioisosterism approach, a virtual screening using T. cruzi CYP51 was performed for 144 NFOH analogues. Additionaly, a qualitative molecular interaction field study was performed, revealing 9 aminoacids in the parasitic enzyme relevant for selectivity. Five novel compounds were synthesized, characterized by melting range, elemental analysis, IR spectroscopy, 1H and 13C NMR as well as HSQC, HMBC, HETCOR and NOESY experiments, in which the signal assigning were aided using molecular modeling techniques Four compounds were tested against T. cruzi amastigotes in infected U2OS cells. All compounds were sufficiently selective towards T. cruzi and showed trypanomicidal activity in low micromolar range. The compound LAPEN-2901 had its structure determined using X-ray crystallography and showed lower toxicity than NFOH and potency similar to benznidazole, but lower efficacy. These results highlight the importance of the 1,2,4-triazolic, thiosemicarbazonic and nitro group moieties for designing new efficient compounds for the chronic phase of Chagas disease.
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Brito, Charles de Lima. "Antichagásicos potenciais: síntese e estudo do comportamento voltamétrico de bioisósteros do nitrofural." Universidade de São Paulo, 2011. http://www.teses.usp.br/teses/disponiveis/9/9138/tde-04042012-131553/.
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A compreensão do mecanismo de redução de compostos nitroheterocíclicos pode ser um parâmetro importante para correlacionar estudos entre a transferência eletrônica e a atividade biológica. O nitrofural (NF), fármaco pertencente ao grupo químico dos 5-nitro- heterocíclicos é ativo contra o Trypanosoma cruzi, agente etiológico da doença de Chagas, mas sua toxicidade impede o seu uso no tratamento desta parasitose. Desta forma, realizaram-se estudos do comportamento eletroquímico de três bioisósteros de NF, com substituição ora no heteroátomo do anel (O e S) ora na carbonila (O e S). As técnicas eletroquímicas de voltametria cíclica (VC), voltametria de pulso diferencial (VPD) e cronoamperometria (CRO) em meio aquoso e empregando eletrodo de carbono vítreo (ECV) como eletrodo de trabalho. A finalidade deste estudo foi compreender a influência do efeito estrutural sobre a atividade redox dos bioisósteros, pois os respectivos comportamentos eletroquímicos podem estar correlacionados com a ação biológica. Todos os processos de redução foram controlados por difusão, com a formação de único pico de redução (Ecp,1), sendo os análogos NT e NTS reduzidos em potencial ligeiramente mais negativo. A comparação dos resultados voltamétricos de NF com os obtidos para cada análogo demonstraram que todos os compostos apresentaram mecanismo de redução similar, envolvendo quatro elétrons, sendo em meio ácido o derivado hidroxilmina (RNHOH) o principal produto formado. Os dados obtidos por VPD e CRO corroboraram com estes resultados. Em meio alcalino e com prévio tratamento do eletrodo de carbono vítreo, constatou-se a formação de um pico de redução reversível, com envolvimento de um elétron para todos os compostos. Este pico refere-se à formação do nitro radical aniônico (R-NO2•-), mostrando-se estável na escala de tempo de medida da técnica de VC. Ademais, realizou-se estudo comparativo do efeito do polimento mecânico no ECV, com diamante e alumina, onde os dois procedimentos não apresentaram efeitos significativos diferentes sobre o comportamento voltamétrico dos análogos estudados. O nitro radical gerado eletroquimicamente em meio aquoso sofre reação de desproporcionamento com cinética de segunda-ordem, seguindo mecanismo ErCi (reação eletroquímica reversível seguida de uma reação química irreversível). Os valores da constante de velocidade k2 desta reação mostraram-se dependentes do pH, confirmando que o nitro radical aniônico é mais facilmente estabilizado em meio alcalino, uma vez que com a diminuição da acidez do meio, a protonação do radical torna-se mais difícil. O composto com a inclusão de dois átomos de enxofre (NTS) apresentou os menores valores de k2 indicando uma cinética de reação de desproporcionamento mais lenta praticamente em toda faixa de pH, com exceção em pH 8, com o qual os valores de k2 não apresentaram diferenças significativas. Portanto, os resultados obtidos neste estudo indicaram claramente a possibilidade de geração e detecção do nitro radical em meio aquoso a partir de compostos nitro-heterocíclicos, distinguindo-se de dados reportados na literatura em que se realizam estes estudos predominantemente em meio não aquoso ou misto.The comprehension of the reduction mechanism of nitroheterocyclic compounds is an important study to know the parameters which can establish the correlation between electron transfer and biological activity. Nitrofural (NF), a drug containing the 5-nitro-heterocyclic moiety, is active against Trypanosoma cruzi, which is the etiologic agent of Chagas disease. Unfortunately, as NF toxicity prevents its use for the treatment against this illness, studies on the electrochemical behavior of three NF bioisosteres were performed. These bioisosteres contained substitutions (O and S) on either the heterocyclic atom or the carbonyl group. The electrochemical techniques herein used were cyclic voltammetry (CV), differential pulse voltammetry (DPV) and chronoamperometry (CRO) in aqueous medium employing a glassy carbon (GCE) as the working electrode. The purpose of this study was to understand the structural influence on the redox activity of these bioisosteres and to suggest the correlation possibilities between the electrochemical behavior and the biological activity. The reduction processes were all diffusion controlled in acidic medium, with the formation of a single peak reduction (Ecp,1), being the NT and NTS analogue reduced at a slightly less negative potential. The comparison between the NF voltammetric results and those obtained with each analogue showed that all compounds presented a similar reduction mechanism, involving four electrons, being the hydroxylamine derivative the main product formed. The obtained data by DPV and CRO corroborated these results. Additionally, in alkaline medium and with previous GCE treatment by polishing a reversible reduction peak formation was observed with the involvement of one electron for all compounds. This peak refers to the nitro-radical anion formation ((R-NO2•-), being stable in the CV time scale. Moreover, a comparative study was carried out on the mechanical effect in the GCE by polishing with diamond and alumina, showing that both procedures had no significant effect on the voltammetric behavior of the compounds. The nitro-radical electrochemically generated in aqueous medium undergoes disproportionation reaction with second-order kinetics, following the ErCi mechanism (reversible electrochemical reaction followed by an irreversible chemical reaction). The constant rate values (k2) for this reaction proved to be pH dependent, confirming that the nitro-radical anion is more easily stabilized in alkaline medium, since the decreasing acidity of the medium hinders the radical protonation. Complementarily, NTS compound showed the lowest values of k2, indicating a slower disproportionation reaction in almost all pH values, except at pH 8, in which the k2 values had no significant difference among all bioisosteres. Therefore, the obtained results in this study clearly showed that nitro-radical anion can be detected and formed in aqueous solution in contrast to what is reported in literature, in which it is predominantly stabilized in non-aqueous solution or in solvent mixture.
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Serafim, Ricardo Augusto Massarico. "Antichagásicos potenciais: estudos sobre a síntese de pró-fármacos recíprocos de bioisósteros do hidroximetilnitrofural e de liberador de óxido nítrico." Universidade de São Paulo, 2011. http://www.teses.usp.br/teses/disponiveis/9/9138/tde-08032013-110857/.
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A doença de Chagas é uma parasitose extremamente negligenciada, cujo agente etiológico é o protozoário Trypanosoma cruzi. Atualmente, 21 países da América Latina são considerados regiões endêmicas, onde 75-90 milhões de pessoas estão expostas à infecção, 15-16 milhões estão infectadas e mais de 41 mil novos casos surgem por ano, entretanto, apenas os fármacos nifurtimox e benznidazol estão disponíveis no mercado. Estes, além da baixa eficácia na fase crônica da parasitose, apresentam diversos efeitos colaterais, sendo que no Brasil apenas o benznidazol é utilizado. Essa carência no arsenal terapêutico contra a doença de Chagas conduz à importância de buscar quimioterápicos mais eficazes para o seu tratamento. Face ao exposto, o objetivo do trabalho foi a síntese de compostos com dupla atividade contra o T. cruzi, utilizando a metodologia da latenciação de fármacos, em que os derivados ativos são bioisósteros de compostos nitro-heterocíclicos, sintetizados em nosso grupo de pesquisa. Os derivados propostos são pró-fármacos recíprocos do nitrofural hidroximetilado (NFOH) e de seus bioisósteros, promissores com respeito à inibição da cruzaína, com o grupamento liberador de óxido nítrico. Podem, deste modo, atuar de forma dupla na inibição da enzima cruzaína e, também, em outras cisteíno-proteases através da ação do óxido nítrico liberado. Além disso, poderiam ser inibidores de tripanotiona redutase, como ocorre com outros nitrocompostos. A síntese dos compostos intermediários foi realizada com êxito, com exceção do composto NFSOH, o qual não foi possível ser isolado. A metodologia solvent-free mostrou-se como alternativa para a síntese do NF e análogos contendo semicarbazona. Utilizaram-se diferentes métodos (direto e indireto) e diversas variações nas condições reacionais para a síntese dos ésteres nitratos correspondentes. No entanto, não se obtiveram os pró-fármacos propostos, provavelmente devido à baixa reatividade dos nitro-heterocíclicos hidroximetilados. Em paralelo, efetuaram-se estudos de Modelagem Molecular para se avaliar a possível interação com o alvo molecular, a cruzaína. A análise dos Mapas de Potencial Eletrostático (MEP) sugeriu maior deficiência eletrônica nos compostos com tiossemicarbazona. Entretanto, estudos de docking mostraram possível preferência de ataque nucleofílico da Cys25 ao grupo éster nitrato em relação à carbonila/tiocarbonila, sugerindo inativação da cruzaína pela formação de S-nitrosotiol.Chagas\' disease is an extremely neglected disease, whose etiologic agent is the protozoan Trypanosoma cruzi. Nowadays, 21 countries in Latin America have been considered endemic area, in which 75-90 million people are exposed to infection, 15-16 million are infected and more than 41 thousands new cases are registered each year. However, nifurtimox and benznidazol are the only drugs available in the market. Besides, their low efficiency in the chronic phase of disease, they cause several side effects and in Brazil only benznidazol is applied. This scarce therapeutic armamentarium shows the importance of seeking for more effective drugs against Chagas\' disease. For these reasons, this study aims the synthesis of compounds with dual activity against T. cruzi, using the prodrug design with the active bioisosters of nitro-heterocyclic, synthesized in our research group. The derivatives proposed are mutual prodrugs of hydroxymethylnitrofurazone (NFOH) and its bioisosters, promising with respect to cruzain inhibition, with NO-releasing group. Thus, they could act with a dual mechanism, in cruzain enzyme and also in other cysteine-proteases through the nitric oxide released action. Besides, they could be trypanothione reductase inhibitors, as stated to other nitro compounds. The synthesis of the intermediate compounds was carried out successfully, except for the NFSOH compound, which could not be isolated. The solvent-free methodology proved to be an alternative for synthesis of nitrofurazone and analogues containing semicarbazone. Different methods (direct and indirect) and several variations in reaction conditions were used for the synthesis of nitrate esters proposed. Nevertheless, the prodrugs were not obtained, probably due to the low reactivity of the hydroxymethyl nitro-heterocyclic employed. At the same time, molecular modeling studies to evaluate the possible interaction with the macromolecular target cruzain were performed. The analysis of electrostatic potential maps (MEP) suggests a greater electronic impairment in compounds containing thiosemicarbazone function. Docking studies, however, showed a possible preference to the nucleofilic attack of Cys25 in the nitrate ester relatively to the carbonyl/tiocarbonyl group, suggesting cruzain inactivation by S-nitrosotiol formation.
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Machado, Patrícia de Almeida. "Atividade leishmanicida de análogos de alcalóides marinhos e bioisósteros do resveratrol em Leishmania amazonensis." Universidade Federal de Juiz de Fora (UFJF), 2013. https://repositorio.ufjf.br/jspui/handle/ufjf/2401.
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O objetivo deste trabalho foi avaliar a atividade leishmanicida de análogos de alcalóides marinhos e bioisósteros do resveratrol em L. amazonensis. Foram testados 12 análogos de alcalóides marinhos 3-alquil piridinas e 7 biosósteros do resveratrol, sendo 4 complexados a ouro, em formas promastigotas de L. amazonensis e em macrófagos peritoneais. Em ambos os casos, a viabilidade celular foi avaliada pelo método colorimétrico do MTT. Os compostos que apresentaram significante atividade antipromastigota e foram seletivos para o parasito, em comparação com a célula hospedeira, foram testados em amastigotas intracelulares de L. amazonensis, cujo efeito dos compostos foi avaliado pela contagem das formas intracelulares. Além disso, foi coletado o sobrenadante para a dosagem de óxido nítrico (NO), através do método de Griess. A maioria dos compostos testados apresentou efeito antipromastigota, destacando os compostos 4 e 5 do grupo dos análogos de alcalóides marinhos, com CI50 de 1,07 e 1,09 µM, respectivamente. Em relação à série dos bioisósteros do resveratrol, destacam-se aqueles complexados a ouro, sendo o composto 17 o mais ativo (CI50 de 5,18 µM). Todos os compostos que foram testados em amastigotas apresentaram atividade, destacando-se, o composto 10 (CI50 = 0,27 µM), dentre os análogos de alcalóides marinhos, e o composto 19, da série dos bioisósteros do resveratrol complexados a ouro (CI50 = 5,77 µM). A maioria dos análogos de alcalóides marinhos mostrou significante toxicidade em macrófagos peritoneais, enquanto somente dois bioisósteros do resveratrol complexados a ouro foram tóxicos para a célula hospedeira. No entanto, todos os compostos testados em amastigotas apresentaram significante seletividade pelo parasito em seu estágio intracelular. Com relação à especificidade das moléculas, os análogos marinhos foram específicos para amastigotas, sugerindo que o alvo desses compostos é exclusivo desse estágio, já a maioria dos bioisósteros do resveratrol complexados a ouro mostraram efeito semelhante em formas promastigotas e amastigotas de L. amazonensis, sugerindo alvos comuns desses compostos nos dois estágios do parasito. Nenhum dos compostos testados induziu significante produção de NO por macrófagos infectados com L. amazonensis, sugerindo que essa molécula não está diretamente relacionada ao efeito antiparasitário. Em resumo, o trabalho mostrou que os compostos testados possuem significativo potencial leishmanicida e abrem perspectivas para estudos em modelos in vivo, bem como estudo do mecanismo de ação.
The aim of this study was to evaluate the leishmanicidal activity of marine alkaloid analogues and bioisosteres of resveratrol in L. amazonensis. We tested 12 3alkylpyridine marine alkaloid analogues of and 7 bioisosteres of resveratrol, 4 complexed to gold, in promastigotes of L. amazonensis and in peritoneal macrophages. In both cases, the viability of the cells was checked using the MTT colorimetric method. Compounds with significant antipromastigote activity and selectivity by the parasite, when compared to the host cell, were tested on intracellular amastigotes of L. amazonensis, which effect of the compounds was determined by counting the number of intracellular parasites. Supernatant was also collected for measure of the nitric oxide (NO), by the Griess method. Most compounds showed antipromastigote effect, especially compounds 4 and 5 of the marine alkaloid analogues, with IC50 of 1.07 and 1.09 µM, respectively. Regarding the bioisosteres of resveratrol, the gold complex 17 was the most active (IC50 of 5.18 µM). All compounds tested in amastigotes exhibited activity, including the compound 10 (IC50 = 0.27 µM), among marine alkaloid analogues, and the compound 19, among gold complexes with bioisosteres of resveratrol (IC50 = 5.77 µM). Most marine alkaloid analogues showed significant toxicity in peritoneal macrophages, while only two bioisosteres of resveratrol complexed to gold were toxic to host cell. However, all compounds tested in amastigotes showed significant selectivity for intracellular parasite. Regarding the specificity of the molecules, marine analogues were specific to amastigote forms, suggesting that the target of these compounds is unique to this stage, while most of bioisosteres of resveratrol complexed to gold showed similar effect on promastigotes and amastigotes of L. amazonensis, suggesting common targets of these compounds in both stages of the parasite. None of compounds induced significant NO production by L. amazonensis-infected macrophages, suggesting that this molecule is not directly related with the antiparasitic effect. In summary, the study showed that the compounds have significant potential leishmanicidal and encourages in vivo studies, as well as the action mechanism.
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Serafim, Ricardo Augusto Massarico. "Antichagásicos potenciais: síntese e modelagem molecular de híbridos de hidrazonas e liberadores de óxido nítrico." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/9/9138/tde-21062016-152156/.
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A doença de Chagas é uma parasitose extremamente negligenciada, cujo agente etiológico é o protozoário Trypanosoma cruzi. Atualmente, 21 países da América Latina são considerados regiões endêmicas, onde 75-90 milhões de pessoas estão expostas à infecção, 6-7 milhões estão infectadas e mais de 41 mil novos casos surgem por ano. Entretanto, apenas os fármacos nifurtimox e benznidazol estão disponíveis no mercado. Estes, além da baixa eficácia na fase crônica da parasitose, apresentam diversos efeitos adversos, sendo que no Brasil apenas o benznidazol é utilizado. Este fato mostra a importância de se ampliar o número de fármacos disponíveis e propor quimioterapia mais eficaz para o tratamento da doença de Chagas. Como forma de contribuir para essa busca, este trabalho objetiva a síntese de compostos híbridos bioisostéricos N-acilidrazônicos e sulfonilidrazônicos, contendo grupo liberador de óxido nítrico, com potencial de interação com cisteíno-proteases parasitárias, tais como a cruzaína. Nestes derivados, os grupos liberadores de óxido nítrico utilizados foram os grupos furoxano (contendo substituinte metílico e fenílico) e éster nitrato. Propôs-se a variação de anéis aromáticos substituídos e não-substituídos, com o intuito de avaliar a possível relação estrutura-atividade (REA) desses análogos. Até o momento, somente os compostos da série N-acilidrazônica tiveram avaliação biológica realizada. Os valores de IC50 dos compostos na forma amastigota do parasita variaram entre >100 a 2,88 µM, sendo este último valor comparável ao fármaco de referência. A atividade inibitória frente à cruzaína foi de 25,2 µM a 2,2 µM. Já a liberação de óxido nítrico foi avaliada pelo método indireto de detecção de nitrato e os valores variaram entre 52,0 µM e 4.232,0 µM. Estes são bem inferiores ao composto padrão, além de não se identificar correlação direta entre a atividade biológica e a liberação de NO. Na sequência, os dois compostos mais ativos (6 e 14) foram submetidos a estudos de permeabilidade e de citotoxicidade. O composto 6 foi considerado o de maior permeabilidade segundo o Sistema de Classificação Biofarmacêutica (SCB) e todos os compostos apresentaram a taxa de fluxo menor que 2, indicando a ausência de mecanismo de efluxo. Na avaliação do potencial citotóxico desses compostos em células humanas, o derivado 6 apresentou índice de seletividade superior ao do benznidazol. Em estudos de modelagem molecular usando análise exploratória de dados (HCA e PCA), propriedades estéricas/geométricas e eletrônicas foram consideradas as mais relevantes para a atividade biológica. Além disso, estudos de docking mostraram que a posição do grupo nitro no anel aromático é importante para a interação com a cruzaína. Ademais o composto 6 não provocou mudanças significativas no ciclo celular e na fragmentação de DNA em células humanas, mostrando-se como líder promissor para futuros estudos in vivo. Atividade tripanomicida, citotoxicidade, potencial de liberação de NO e estudos de permeabilidade dos 23 derivados sulfonilidrazônicos e ésteres nitrato estão sendo avaliados.Chagas disease is an extremely neglected parasitic disease whose etiologic agent is the protozoan Trypanosoma cruzi. Currently 21 Latin American countries are considered endemic regions, where 75-90 million people are exposed to infection, 6-7 million are infected and more than 41,000 new cases occur annually. However only nifurtimox and benznidazole are available on the market. These drugs, besides low efficacy in the chronic phase of the parasite have numerous adverse effects, and in Brazil only benznidazole is used. This fact shows the importance of increasing the number of drugs available and propose more effective chemotherapy for the Chagas disease treatment. As a contribution to the problem, this study aims the synthesis of biososteric compounds from N-acylhydrazone and sulfonylhydrazone, which have the potential to interact with parasitic cysteine protease, such as cruzain, containing nitric oxide releasing groups, which also has inhibitory activity in this enzyme class. In these derivatives nitric oxide releasing groups used were furoxan (containing methyl and phenyl substituent) and nitrate ester groups. The variation of aromatic rings substituted and unsubstituted was proposed in order to evaluate the possible structure-activity relationship (SAR) of these analogs. Only N-acylhydrazone series had its biological profile evaluated up to now. The IC50 values of the compounds against the amastigote form of the parasite ranged from >100 µM to 2.88 µM, the last value being comparable to that of reference drug. Cruzain inhibitory activity ranged from 25.2 µM to 2.2 µM. The nitric oxide releasing potential was evaluated using the indirect method of detection and nitrate values ranged between 52.0 µM and 4,232.0 µM. These results are below than those of the standard compound, and there is no direct correlation between the biological activity and nitric oxide releasing potential as well. Further, the two most active compounds (6 and 14) were submitted to permeability and cytotoxicity studies. Compound 6 showed the highest permeability value according to Biopharmaceutics Classification System (BCS), and both compounds showed flow rate lower than 2, indicating no efflux mechanism. In the cytotoxicity studies of these compounds in human cells, the derivative 6 showed selectivity index greater than benznidazole. In molecular modeling studies using exploratory data analysis (HCA and PCA) steric/geometric and electronic properties were considered the most relevant for biological activity. In addition, docking studies were performed and showed that the position of the nitro group on the aromatic ring is important for the interaction with cruzain. Compound 6 did not cause significant changes in cell cycle and DNA fragmentation in human cells, showing to be a promising lead compound for future in vivo studies. Trypanocidal activity, cytotoxicity assay, NO releasing potential and permeability studies of the 23 sulfonylhydrazones and nitrate ester derivatives are being evaluated.
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Tréguier, Bret. "Développement de nouveaux analogues structuraux de l’isocombrétastatine A-4 : conception, synthèse et évaluation biologique." Thesis, Paris 11, 2012. http://www.theses.fr/2012PA114805.
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Lors de son développement, une tumeur ne peut survivre sans passer par une étape invasive afin de subvenir à ses besoins en nutriment et en oxygène. Cette étape, appelé angiogénèse tumorale, conduit à la formation de vaisseaux sanguins dits « tumoraux », différents des vaisseaux sanguins normaux. Afin de stopper la croissance de la tumeur, il est possible de détruire les vaisseaux sanguins tumoraux formés pendant l’angiogénèse tumorale grâce à des molécules antivasculaires. Ces molécules vont désorganiser la structure du vaisseau et diminuer le flux sanguin au sein de la tumeur pour mener à la nécrose de cette dernière. Parmi ces molécules antivasculaires,la prodrogue phosphate de la combrétastatine A-4 naturelle (CA-4) est le composé actuellement le plus efficace(en développement clinique de phase III contre le cancer de la thyroïde). L’isocombrétastatine A-4 (isoCA-4),possédant une structure de type 1,1-diaryléthylène, est un analogue très puissant développé au laboratoire. Cette molécule est isomère de la CA-4 et permet d’obtenir les mêmes activités biologiques que la CA-4. L’objectif de cette thèse est d’étudier ce motif 1,1-diaryléthylène dans le cadre de molécules cytotoxiques en synthétisant et en évaluant in vitro plusieurs séries de molécules de type « iso ». L’autre partie de cette thèse est dédiée à la synthèse d’analogues hétérocycliques de l’isoCA-4, qui permettront de réaliser les premières études de relation structure-activité sur l’isoCA-4, où son cycle B a été remplacé par un hétérocycle. Ce travail nous a permis de confirmer que la structure de l’isoCA-4 peut servir de base de travail pour développer d’autres agents antivasculairesFor a tumor, the angiogenesis is a vital step for its development. The spread of the tumor is necessary characterized by an extension of the surrounding vasculature, in order to provide the nutriments and the oxygen required to the growth of the tumor. Resulting from the angiogenesis, the new tumorous blood vessels formed represent an excellent target to treat cancer by aiming specifically at the heart of the tumor. By means of vascular disrupting agents (VDA), it is possible to cut the tumor off the blood flow to trigger the necrosis within the tumor. Among the current VDA, the natural combretastatin A-4 (CA-4) is a strong compound that exhibits excellent antitumoral activities. An isomer of the CA-4, the isocombretastatin A-4 (isoCA-4), was developed inour laboratory to propose an alternative and a new family of VDA. The isoCA-4 is characterized by a 1,1-diarylethylene core, which we studied in this thesis, through 3 series of molecules related to this new structure inmedicinal chemistry. We also synthesized heterocyclic analogues of the isoCA-4, in order to explore the capacity of the isoCA-4 to serve as a basis for developing new antimitotic compounds
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Compain, Guillaume. "Cyclisation et hydrofluoration de composés azotés insaturés en milieu superacide." Thesis, Poitiers, 2012. http://www.theses.fr/2012POIT2287/document.
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Du fait de l'extrême acidité des milieux superacides, le comportement des composés organiques y est particulièrement singulier, et en particulier celui des composé azotés. Ces milieux permettent d'accéder par polyprotonation à des intermédiaires superélectrophiles polycationiques, capables d'être piégés par des nucléophiles faibles, comme les ions fluorures solvatés du milieu ou des aromatiques désactivés. L'activation superélectrophile permet en outre d'accéder à une régiosélectivité unique en rendant certains sites réactifs, insensibles dans les milieux acides plus classiques.Dans la première partie de ce travail est étudiée une réaction d'addition anti-Markovnikov sur des anilines N-allyliques dans le mélange HF/SbF5. Une étude mécanistique a été réalisée incluant la modélisation d'intermédiaires réactionnels, des expériences de RMN in situ ainsi que des réactions avec des substrats marqués. Grâce à cette étude, une nouvelle réaction de type Friedel-Crafts permettant d'accéder à des tétrahydroquinolines désactivées a été mise au point. De plus, en modifiant les conditions opératoires, la synthèse d'anilines β-fluorées a également pu être réalisée. Ces réactions ont ensuite été appliquées à la synthèse de nouveaux composés hétérocycliques.La deuxième partie est consacrée au développement d'une nouvelle réaction d'hydrofluoration dynamides dans l'acide fluorhydrique anhydre. Cette méthodologie permet d'accéder à des (E)-α-fluoroènamides orginales avec un excellente régio- et stéréo-sélectivité. Par analogie avec les fluorooléfines qui sont connues pour mimer les fonctions amides, ces composés sont potentiellement de nouveaux bioisostères rigides d'urées, avec des appThanks to the extrem acidity of superacid media, the behavior of organic compound in these conditions is especially original. These media provide access by polyprotonation to superelectrophilic polycationic intermediates able to be trapped by very weak nucleophiles such as solvated fluoride ions or deactivated aromatic. In addition, the superelectrophic activation allowed to access to a unique regioselectivity, making some classically unreactive sites very reacive in these conditions.In the first part of this work, an anti-Markovnikov addition of N-allyl anilines in the HF/SbF5 mixture is studied. A mechanistic study was performed including the modeling of reaction intermediates, in situ NMR experiments and reactions with labeled substrates. Through this study, a new Friedel-Crafts type reaction was perform and applied to deactivated tetrahydroquinoline synthesis. In addition, the synthesis of β-fluorinated anilines could also be performed. These reactions were then applied to the synthesis of new heterocyclic compounds.The second part deals with the developement of a new hydrofluorination reaction of yanmides using anhydrous fluorhydric acid. This methodology allowed the synthesis of original (E)-α-fluoroenamides with an excellent regio- and stereo-selectivity. By analogy with fluoroolefins which are known to be mimics of amides, these compounds are potentially new rigid bioisosters of ureas with further potent applications in medicinal chemistry
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Jovana, Francuz. "Nove izostere i bioizostere prirodnih stiril-laktona: dizajn, sinteza i antiproliferativna aktivnost." Phd thesis, Univerzitet u Novom Sadu, Prirodno-matematički fakultet u Novom Sadu, 2015. https://www.cris.uns.ac.rs/record.jsf?recordId=93661&source=NDLTD&language=en.
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U radu su ostvarene višefazne sinteze većeg broja analoga prirodnih stiril-laktona (+)-goniofufurona i 7-epi-(+)-goniofufurona polazeći iz D-glukoze.Ispitana je in vitro citotoksičnost sintetizovanih analoga prema devetmalignih i jednoj zdravoj ćelijskoj liniji. Uspostavljeni su korelacioni odnosiizmedju strukture i antiproliferati vne aktivnosti sintetizovanih proizvoda, pored toga uradjeni su i dodatni biološki testovi koji se odnose na dokazivanje mehanizma citotoksičnog dejstva pomenutih stiril-laktona i analoga.Multistep synthesis of a number of natural styryl lactones goniofufurone and 7-epi-goniofufurone analogues was achieved starting f rom D-glucose. In vitro cytotoxicity of newly synthetized analogues against nine human tumour cell lines and against a single normal cell line was evaluated. Structure-activity relationships were established for both natural products and analogues. Some additional biological tests related to the cell mechanisms underlying the cytotoxicity of the mentioned styryl lactones and analogues, were also carried out.
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Desaphy, Jérémy. "L'analyse structurale de complexes protéine/ligand et ses applications en chémogénomique." Phd thesis, Université de Strasbourg, 2013. http://tel.archives-ouvertes.fr/tel-00997394.
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Comprendre les interactions réalisées entre un candidat médicament et sa protéine cible est un enjeu crucial pour orienter la recherche de nouvelles molécules. En effet, ce processus implique de nombreux paramètres qu'il est nécessaire d'analyser séparément pour mieux comprendre leurs effets.Nous proposons ici deux nouvelles approches observant les relations protéine/ligand. La première se concentre sur la comparaison de cavités formées par les sites de liaison pouvant accueillir une molécule. Cette méthode permet d'inférer la fonction d'une protéine mais surtout de prédire " l'accessibilité " d'un site de liaison pour un médicament. La seconde tactique se focalise sur la comparaison des interactions non-covalentes réalisées entre la protéine et le ligand afin d'améliorer la sélection de molécules potentiellement actives lors de criblages virtuels, et de rechercher de nouveaux fragments moléculaires, structuralement différents mais partageant le même mode d'interaction.
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Landagaray, Elodie. "Conception, synthèse et évaluation pharmacologique d’antidépresseurs potentiels : ligands mixtes des récepteurs mélatoninergiques MT1/MT2 et des récepteurs sérotoninergiques 5-HT2c." Thesis, Lille 2, 2014. http://www.theses.fr/2014LIL2S063/document.
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La dépression est l’un des troubles mentaux les plus fréquents de nos jours. C’est une maladie liée en général à un déficit en neurotransmetteurs monoaminergiques (sérotonine, noradrénaline et dopamine). Les antidépresseurs actuels agissant via des mécanismes monoaminergiques présentent de nombreux effets secondaires et peuvent conduire à une accoutumance. L’une des approches impliquerait le ciblage des récepteurs mélatoninergiques afin de resynchroniser les rythmes circadiens qui sont perturbés dans certaines pathologies du système nerveux central, notamment la dépression. La conception de ligands non monoaminergiques et possédant des propriétés chronobiotiques constituerait une stratégie prometteuse.L’agomélatine (Valdoxan®) issue d’une collaboration entre le laboratoire de chimie thérapeutique (EA4481 - GRIIOT) et les laboratoires Servier est commercialisée depuis 2009 pour le traitement de la dépression majeure. Ce bioisoster naphtalénique de la mélatonine possède un mécanisme d’action innovant. Elle se distingue par ses propriétés agoniste non sélectif des récepteurs mélatoninergiques MT1 et MT2 et antagoniste des récepteurs 5-HT2c.L’objectif de ce travail réside dans la conception et la synthèse de nouveaux ligands successeurs de l’agomélatine présentant un profil pharmacologique et pharmacocinétique amélioré. Différentes pharmacomodulations ont été réalisées sur l’agomélatine. Les stratégies de «Drug Design» notamment le principe de bioisostérie ont été appliquées, nous permettant ainsi la synthèse de nouvelles familles de composés présentant des profils pharmacologiques intéressantsNowadays, depression related to a deficit in nonoaminergic neurotransmitters, is the most frequent mental illness. Available antidepressive drugs acting through monoamnergic mechanisms possess a lot of side effects and can lead to an addiction. One approach involves targeting melatoninergic receptors to resynchronize circadian rhythms, which are known to be perturbed in some pathology related to nervous central system as depression. So conception of non-monoaminergic ligands with chronobiotic properties would constitute a promising strategy.Agomelatine (Valdoxan®) a novel antidepressant developed by Servier and our laboratory (EA4481 - GRIIOT) was granted marketing authorization in 2009 for the treatment of major depressive disorder. This naphthalen analogous of melatonin possess an innovative mechanism. It acts as a non selective melatoninergic MT1/MT2 receptors agonist and a serotonin 5-HT2c receptor antagonist.The aim of this work is to design and synthesize new potential successors of agomelatine with an improved pharmacological and pharmacokinetic profile. Drug Design strategies such as bioisosterism were applied to allow the elaboration of new series of compounds with interesting pharmacological profiles
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Hesse, Almut. "Entwicklung immunchemischer Methoden zur Spurenanalytik der Sprengstoffe Nitropenta und Trinitrotoluol." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät, 2017. http://dx.doi.org/10.18452/17773.
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Der Sprengstoff PETN ist äußerst schwer zu detektieren. Ein verbesserter anti-PETN-Antikörper wurde durch Anwendung des Bioisosterie-Konzepts entwickelt. Diese polyklonalen IgGs sind sehr selektiv und sensitiv. Die Nachweisgrenze des ELISAs beträgt 0,15 µg/L. Der Messbereich des Immunoassays liegt zwischen 1 und 1000 µg/L. Die Antikörper sind recht pH-stabil als auch robust gegen Lösungsmittelzusätze. Für die Umweltanalytik von TNT wurde eine HPLC-kompatible Affinitätssäule mit porösem Glas als Trägermaterial hergestellt. Um die anti-TNT-Antikörper selektiv aus den TNT-Seren zu isolieren, wurde eine Trennung an einer Dinitrophenyl-Affinitätssäule durchgeführt. Zur Optimierung der Kopplungsmethode wurden orangefarbene Dabsyl-Proteine synthetisiert und auf der Oberfläche gebunden. Die Färbung wurde als Indikator für die Ligandendichte verwendet. Wegen der hohen Affinitätskonstanten der anti-TNT-IgGs lässt sich TNT nicht reversibel von der TNT-Affinitätssäule eluieren. Daher wurde eine neuartige Elutionsmethode entwickelt, die thermische Online-Elution. Die maximale Kapazität einer TNT- Affinitätssäule betrug 650 ng TNT bzw. 10 µg/mL Säulenvolumen. Um die Ligandendichte der TNT-Affinitätssäulen zu bestimmen, wurde ein neues Verfahren entwickelt, da die spektroskopischen Proteinbestimmungsmethoden nicht geeignet waren. Zur Proteinbestimmung wurde eine HPLC-Trennung der Aminosäuren Tyr und Phe ohne vorherige Derivatisierung entwickelt. Die Proteinhydrolysezeit wurde durch Einsatz einer Mikrowelle von 22 h auf 30 min verkürzt. Zur internen Kalibrierung wurden HTyr und FPhe verwendet. Die Nachweisgrenze bei 215 nm ist sowohl für Tyr als auch für Phe 0,05 µM (~ 10 µg/L). Dieses neue Verfahren, das als Aromatische Aminosäureanalyse (AAAA) bezeichnet werden kann, wurde zur Proteinbestimmung von homogenen Proben mit NIST-BSA validiert, wobei die Nachweisgrenze für Proteine 16 mg/L (~ 300 ng BSA) ist. Die relative Standardabweichung incl. der Hydrolysestufe beträgt 5%.The explosive Pentaerythritol tetranitrate (PETN) is extremely difficult to detect. An improved antibody against PETN was developed by using the bioisosteric concept. These polyclonal antibodies are highly selective and sensitive. The limit of detection (LOD) of the ELISA was determined to be 0.15 µg/L. The dynamic range of the assay was found to be between 1 and 1000 µg/L. The antibodies are sufficiently pH-stable and resistant to solvent additives. An HPLC-compatible TNT-affinity column with porous glass as support material was prepared for the environmental analysis. In order to isolate the anti-TNT antibodies of the TNT sera a separation was carried out on a dinitrophenyl-affinity column. To optimize the immobilization method, orange-coloured dabsyl proteins were synthesized and bound to the surface. The colour intensity was found to be an indicator for the immobilization rate. In consequence of the high affinity constants of the anti-TNT antibodies, TNT can''t elute by a typical acidic elution step. Therefore, a novel separation approach, the thermal online-elution was developed. The maximum capacity of an affinity column was 650 ng TNT or 10 µg/mL of column volume. To quantify the immobilization rate of proteins, a new method has been developed, because the usual protein determination methods were unsuitable. Therefore an HPLC separation method of Tyr and Phe was developed without prior derivatization. Two internal standard compounds, HTyr and FPhe, were used for calibration. The LOD was estimated to be 0.05 µM (~ 10 µg/L) for Tyr and Phe at 215 nm. The protein hydrolysis time was reduced from 22 h to 30 min using microwave technique. This procedure, that was termed aromatic amino acid analysis (AAAA), has been validated for protein determination of homogeneous samples with NIST-BSA. The LOD for proteins was calculated to be below 16 mg/L (~ 300 ng BSA absolute). The relative standard deviation, including the hydrolysis step, is 5%.
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Handmann, Vera Iris. "Studien zur C/Si-Bioisosterie." Doctoral thesis, 2002. https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-4719.
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Im Rahmen der vorliegenden Arbeit wurden Beiträge zur C/Si-Bioisosterie und zur asymmetrischen Synthese neuer siliciumhaltiger alpha-Aminosäuren geleistet. Im Vordergrund der Untersuchungen stand die Entwicklung neuer präparativer Methoden zur Darstellung siliciumhaltiger Wirkstoffe und die Untersuchung ihrer pharmakologischen Wirksamkeit sowie die Synthese racemischer und enantiomerenreiner siliciumhaltiger alpha-Aminosäuren des beta-(Trimethylsilyl)alanin-TypsThis work describes contributions to the field of C/Si bioisosterism and to the asymmetric synthesis of novel silicon-containing alpha-amino acids. The aim of these investigations was the development of new preparative methods for the synthesis of silicon-containing drugs and their pharmacological evaluation as well as the synthesis of racemic and enantiomerically pure silicon-containing alpha-amino acids of the beta-(trimethylsilyl)alanine type