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1
Azmus, Dora J. Taylor. "Synthesis of polybenzimidazoles from monomers containing flexible linkages." Thesis, Corvallis, Oregon : Oregon State University, 1992. http://handle.dtic.mil/100.2/ADA256976.
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Thesis (M.S.)--Oregon State University, 1993.<br>Description based on title screen as viewed on April 8, 2009. "Completed 13 May 1992, Commencement June 1993." Includes bibliographical references (p. 73-75). Also available in print.
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Robinson, A. G. "Synthesis and reactions of 2H-benzimidazoles." Thesis, University of Salford, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.356186.
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Wathey, William B. "The synthesis of benzimidazoles of medicinial interest." Thesis, Cardiff University, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.329643.
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The aim of this programme was to design and synthesize triazinobenzimidazoles that are analogous to the antihypertensive agents, hydralazine and dihydralazine. Retrosynthetic analysis of these analogues showed that the key intermediates in the synthesis were the novel [1,2,4]triazino[4,5-a]benzimidazol-l-ones and the related 1,4-diones. Existing routes to this tricyclic ring system were either limited in scope or needed expensive starting materials. Therefore, a new synthetic route to these compounds was developed using the readily available 2-acylbenzimidazoles as starting materials. These acyl derivatives were converted to hydrazones, ethoxycarbonylhydrazones and benzimidazole-2-carboxylic acid ethoxycarbonylhydrazides. The substituted hydrazines were cyclized to the desired tricyclic lactam intermediates either thermally, or acylatively using ethyl chloroformate in pyridine. The versatility of these cyclization methods has been demonstrated by the synthesis of a variety of novel N-2 substituted [1,2,4]triazino[4,5-a]benzimidazol- 1-ones which may or may not have a substituent at C-4. In addition, it has been shown that these types of cyclizations provide a better route to existing triazinobenzimidazoles. Although attempts to chlorinate or thiate these lactams were unsuccessful, use of the dithio analogue of ethyl carbazate, methyl dithiocarbazate, afforded sulphur-containing hydrazones which were cyclized to the desired [1,2,4]triazino[4,5-a]benzimi dazole-1-thiones. Displacement of the enolized 1-thione by hydrazine produced the desired target molecules, 1-hydrazino- [1,2,4]triazino[4,5-a]benzimidazoles. In preliminary screening, these compounds exhibited in vivo vasodilatory activity. In an attempt to vary the 4-substituent of the tricyclic system further, the synthesis of a variety of modified 2-acylbenzimidazoles was undertaken. In particular, the structure and reactions of one of these modified ketones, 2-bromoacetylbenzimidazole, was investigated in an attempt to explain its bromination pattern. Other workers have suggested that the unusual bromination pattern of 2-acetyl and 2-bromoacetylbenzimidazole may arise from the influence of intramolecular hydrogen bonding between the imine proton and the carbonyl group. However, a computer-aided reinvestigation of this reaction has shown that a more plausible intermediate is an intramolecularly hydrogen bonded enol of the ketone. The synthesis of two novel triazepinobenzimidazole ring systems has been examined. The acylative-cyclization (ethyl chloroformate-pyridine) developed for the preparation of the novel triazines has been extended to the synthesis of the hitherto unknown [1,2,4]triazepino[4,5-a]benzimidazole ring system. A series of new 1,2-diacylbenzimidazoles were prepared as precursors to [1,2,5]triazepino[5,4-a]benzimidazoles. However, attempts to add hydrazine across the dicarbonyl groups gave only novel benzimidazole hydrazine or hydrazide derivatives instead of the desired triazepinobenzimidazoles. Many of the compounds described in this thesis have been screened for possible pharmacological activity.
4
Bowles, Steven E. "Synthesis and characterization of annelated nitronyl nitroxides /." Thesis, Connect to this title online; UW restricted, 2005. http://hdl.handle.net/1773/11611.
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Taylor, S. L. "An investigation of catalysis in the Ladenburg synthesis of benzimidazoles." Thesis, Manchester Metropolitan University, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.233017.
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Wahedy, Kanan Mahmoud. "Methodology for synthesis of novel bis-and oligo (benzimidazoles)." Thesis, University of Manchester, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.684999.
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Hubbard, Jeremiah W. "Synthesis of substituted 2-vinyl and 2-phenylbenzimidazoles and progress towards the synthesis of natural products ht-13-A and ht-13-B." Morgantown, W. Va. : [West Virginia University Libraries], 2008. https://eidr.wvu.edu/etd/documentdata.eTD?documentid=6051.
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Thesis (Ph. D.)--West Virginia University, 2008.<br>Title from document title page. Document formatted into pages; contains xi, 179 p. : ill. Includes abstract. Includes bibliographical references (p. 88-94).
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Hazelton, J. C. "Reactions of 2H-benzimidazoles and synthesis of some potential anthelmintics." Thesis, University of Salford, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.234629.
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Khan, Aqeel Ahmad. "Synthesis of novel oligomeric bis-benzimidazoles for their biological evaluation." Thesis, University of Manchester, 2012. https://www.research.manchester.ac.uk/portal/en/theses/synthesis-of-novel-oligomeric-bisbenzimidazoles-for-their-biological-evaluation(769832e2-2892-4bcb-b739-8929b4da5ca8).html.
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Benzimidazoles are heterocyclic compounds. Symmetrical and unsymmetrical benzimidazoles/oligomers are minor groove DNA sequence selective binding compounds. Distamycin A and netropsin are examples of naturally occurring DNA binders. Hoechst 33258 (Bis–benzimidazole) is a synthetic minor groove A-T sequence selective reagent and has in vivo activity by inhibiting the topoisomerase II enzyme. The targets in this research work were to synthesise extended analogues of Hoechst with structural modifications (amide bond) or amide-linked dimers with a view to identifying new potential ligands. To synthesise a library of novel bis-benzimidazoles (analogues of Hoechst) several methods were used. For C5–C2 direct linkage aldehyde synthesis via ester, Weinreb amide reduction, condensation of acids with diamine by Eaton’s reagent were applied. Cyclization of amide-linked benzimidazoles (amide bond between carboxylic acid of C5 benzimidazole and diamine), an indirect method of bis-benzimidazole synthesis was also used to prepare a library of novel bis-benzimidazoles giving a series of novel intermediates. Higher molecular weight oligomeric structures (Linked by amide bond either between C5-C5 or C5-C2) were prepared by using (EDCI / HOBt) or (HBTU / DIPEA). A library of novel amide-linked, oligomeric analogues of Hoechst were also synthesised by coupling bis-benzimidazole building blocks bearing reactive groups at positions 2 or 5. Amine (by the reduction of a nitro precursor) or carboxylic acid (from ester hydrolysis) was coupled with monomeric amino or carboxylic acid benzimidazole derivatives using different peptide coupling reagents. Further structural modifications were performed either by reduction of an ester on a bis-benzimidazole or by the reaction of hydrazine with the ester or acid to have an additional flexible spacer (amide bond) with reactive amine to address the issue of solubility. SPR (Surface Plasmon Resonance) was employed to evaluate more than 30 different analogues in comparison with Hoechst 33258 in terms of their DNA binding affinity using three different oligonucleotides having A2T2, A3T3, A4T4 sequences. The data revealed that compounds with charged specie at peripheral groups are better binders in the grooves of DNA.
10
Alaqeel, Shatha. "Synthesis of novel dimeric and oligomeric benzimidazoles targeted to nucleic acid minor groove binding." Thesis, University of Manchester, 2010. https://www.research.manchester.ac.uk/portal/en/theses/synthesis-of-novel-dimeric-and-oligomeric-benzimidazoles-targeted-to-nucleic-acid-minor-groove-binding(5e5b7b9a-72fb-4941-80ec-0a28a3c1b098).html.
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Amido-oligopyrroles/imidazoles and dimeric benzimidazoles are heterocyclic compounds which are nucleic acid minor groove binding agents. The targets for this project were symmetrical and unsymmetrical amide-linked di- and tri- and tetrameric benzimidazoles to evaluate as potential DNA binding agents. Syntheses involved linkage between C2 and C5 positions of 2-carboxy, 5-carboxy or 2,5-dicarboxy and 2-amino, 5-amino or 2,5-diamino-bearing benzimidazoles. This matrix of substrates could be coupled directly C2-C5 by amide linkage, or these same precursors could also be dimerized symmetrically using small bifunctional linkers (diamine or diacid), affording symmetrical C2-C2 or C5-C5 dimer types of orientation, such as head-to- head, and tail-to tail systems. Monomeric building block benzimidazoles were prepared by condensation of o- phenylene diamines with either aldehydes or carboxylic acids affording the corresponding C2 or C5 amino and C5 carboxybenzimidazoles. 2- Carboxybenzimidazoles were however prepared by condensation of o-phenylene diamines with trichloroacetimidate followed by hydrolysis. New different novel symmetrical and unsymmetrical-bis(benzimidazole) libraries (C2-C2, C5-C5 and C5- C2 orientation) were prepared via coupling of different aminobenzimidazoles with different carboxybenzimidazoles from the matrix of available monomers. Novel tris(benzimidazoles) with differently linked orientations were prepared either by coupling one equivalent of 2,5-dicarboxybenzimidazole with two equivalents of aminobenzimidazole or coupling one equivalent of 2,5-diaminobenzimidazole with two equivalents of carboxybenzimidazole. A second set of novel tris(benzimidazoles) was prepared via reduction of a nitro- to amino bearing dimer followed by coupling with another carboxybenzimidazole monomer. Novel symmetrical tetra(benzimidazoles) (C2-C2-C2-C2 and C5-C2-C2-C5 orientation) were synthesized via either coupling one equivalent 2-dicarboxy dimeric benzimidazole with two equivalents of 2 or 5-aminobenzimidazole or via coupling one equivalent of 2-diaminobis(benzimidazole) with two equivalents of 2 or 5- carboxybenzimidazoles. Novel symmetrical bis(benzimidazoles) piperidine derivatives were synthesized via coupling one equivalent of 2-dicarboxy dimericbenzimidazole with two equivalents of piperidine derivatives. Forty oligomeric benzimidazoles were evaluated using Surface Plasmon Resonance (SPR) for binding to a series of three oligonucleotides containing A2T2, or A3T3 or A4T4 sequences. Data are presented showing the identification of four optimum ligands from a screen of 40, primarily 2L2552L2 tetramers but also several 2L5 dimers and dimeric 5,5-units without terminal additional benzimidazoles.
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R, Aunós Clàudia [Verfasser]. "Synthesis and Biological Investigation of Antifungal Peptides and Benzimidazoles / Clàudia R. Aunós." Tübingen : Universitätsbibliothek Tübingen, 2019. http://d-nb.info/1227963041/34.
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Barnard, Linley Nicole. "Synthesis and profiling of antimalarial side-chain modified pyrido[1,2-a]benzimidazoles." Master's thesis, University of Cape Town, 2017. http://hdl.handle.net/11427/27245.
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The currently available malaria drugs in the market are unsatisfactory in many respects. Shortcomings include costly treatments, toxicity and various side effects. The rapid rise of resistant strains of Plasmodium falciparum, particularly in South-East Asia, has rendered even the most promising treatment regimens ineffective. Therefore, there is an urgent need to explore and develop new antimalarial drugs preferably with novel mechanisms of action, multistage activity, good safety profiles and efficacy at low doses. To address this need, structure activity relationship (SAR) and structure property relationship (SPR) studies were carried out on a novel antimalarial chemotype, namely the pyrido[1,2-a]benzimidazoles (PBI) class of compounds. A frontrunner compound based on the PBI scaffold was previously found to possess potent antiplasmodial activity in vitro [IC₅₀(Pf NF54) = 0.11 μM; IC₅₀(Pf K1) = 0.12 μM] and promising oral efficacy (95% at 4×50 mg/Kg p.o) in the in vivo mouse P. berghei model. However, pharmacokinetic (PK) studies showed oral-limited absorption attributed to poor dissolution or solubility. Thus a series of derivatives was synthesized by making structural modifications to the parent PBI scaffold by distorting the symmetry through introduction of small groups in the C-2 position (Figure i), in an effort to identify derivatives with improved solubility properties, while retaining antiplasmodial activity. The synthesized derivatives displayed good antiplasmodial activity against the chloroquine-sensitive (NF54) strain of P. falciparum and selected compounds against the multi-drug resistant (K1) strain. However, substitutions at the C-2 position resulted in derivatives with improved solubility at the expense of antiplasmodial activity and metabolic stability. In an effort to investigate the factors responsible for improvement in solubility, the dihedral angles of the optimized structures were derived using density functional theory (DFT) calculations (B3LYP/6- 31G*). The calculated dihedral angle of compound 6.4 was compared to the experimentally determined dihedral angle from the single X-ray crystal structure of 6.4. A weak correlation (R² = 0.4) between kinetic solubility and dihedral angle was observed and this suggests that there are many factors that influence solubility and that dihedral angle is just one them.
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Alasmary, Fatmah Ali Saeed. "Synthesis and evaluation of selected benzimidazole derivatives as potential antimicrobial agents : an investigation into the synthesis of substituted benzimidazoles and their evaluation in vitro for antimicrobial activity." Thesis, University of Bradford, 2013. http://hdl.handle.net/10454/6325.
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Microbe resistence is a serious issue, especially as they have become resistant to most well known drugs. Therefore this is considered as a global problem and is now dealt with at a poitical level. Since no new classes of antimicrobial agents have been discovered in the past three deacdes, the development of new drugs is extremely urgent. Therefore the aim of this project was to synthesise derivatives of benzimidazole, and then assesses their antimicrobial activities in vitro by using disc (well) diffusion and MICs tests. A total of 69 benzimidazole derivatives, with substituents at positions 1, 2, and 5, were synthesised, characterised and tested against selected bacteria and fungi. In addition, six bezimidazole silver complexes were prepared and evaluated for their antimicrobial behavior. The SAR showed that the antimicrobial activity of the compounds depended on the substituents attached to the bicyclic heterocycle. Some promising results were obtained. In particular, 5 compounds displayed antibacterial activity against two MRSA strains with MIC values corresponding to ciprofloxacin, which can be considered significant. The compounds have some common features; four possess 5-chloro or 5-bromo substituents; two are derivatives of (S)-2- ethanaminebenzimidazole and the others are derivative of one 2-(chloromethyl)-1Hbenzo[d]imidazole, (1H-benzo[d]imidazol-2-yl)methanethiol and 2-(methoxymethyl)-1-methyl-1H-benzo[d]imidazole. The results from the antifungal screening were very interesting as there were 26 compounds, including two silver complexes, which were potent fungicides against the selected fungal species. They showed equivalent or greater potentency in their MIC values than amphotericin B. In particular, the 5-fluoro, 5-chloro and 5-bromo benzimidazole showed broad spectrum activity.
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Alasmary, Fatmah A. S. "Synthesis and evaluation of selected benzimidazole derivatives as potential antimicrobial agents. An investigation into the synthesis of substituted benzimidazoles and their evaluation in vitro for antimicrobial activity." Thesis, University of Bradford, 2013. http://hdl.handle.net/10454/6325.
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Microbe resistence is a serious issue, especially as they have become resistant to
most well known drugs. Therefore this is considered as a global problem and is now
dealt with at a poitical level. Since no new classes of antimicrobial agents have
been discovered in the past three deacdes, the development of new drugs is
extremely urgent. Therefore the aim of this project was to synthesise derivatives of
benzimidazole, and then assesses their antimicrobial activities in vitro by using disc
(well) diffusion and MICs tests.
A total of 69 benzimidazole derivatives, with substituents at positions 1, 2, and 5,
were synthesised, characterised and tested against selected bacteria and fungi. In
addition, six bezimidazole silver complexes were prepared and evaluated for their
antimicrobial behavior.
The SAR showed that the antimicrobial activity of the compounds depended on the
substituents attached to the bicyclic heterocycle. Some promising results were
obtained. In particular, 5 compounds displayed antibacterial activity against two
MRSA strains with MIC values corresponding to ciprofloxacin, which can be
considered significant. The compounds have some common features; four possess
5-chloro or 5-bromo substituents; two are derivatives of (S)-2-
ethanaminebenzimidazole and the others are derivative of one 2-(chloromethyl)-1Hbenzo[d]imidazole, (1H-benzo[d]imidazol-2-yl)methanethiol and 2-(methoxymethyl)-1-methyl-1H-benzo[d]imidazole.
The results from the antifungal screening were very interesting as there were 26
compounds, including two silver complexes, which were potent fungicides against
the selected fungal species. They showed equivalent or greater potentency in their
MIC values than amphotericin B. In particular, the 5-fluoro, 5-chloro and 5-bromo
benzimidazole showed broad spectrum activity.<br>Saudi Culture Bureau and King Saud University
15
Kim, Young Jun. "Kinetic and mechanistic investigations of polyimide formation and characterization of their blends with polybenzimidazoles." Diss., Virginia Tech, 1992. http://hdl.handle.net/10919/37417.
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This dissertation describes kinetic and mechanistic studies of high performance polyimide formation, synthesis and characterization of fully cyclized, molecular weight and end group controlled polyimides, and investigations of high performance polymer blends based upon polyimides and polybenzimidazole.
Imidization kinetics were successfully followed by the quantitative non-aqueous titration of the amic acid functional groups as a function of reaction conditions. The homogeneous solution imidization processes were described by auto-acid catalyzed second order kinetics. The effects of heteroatom bridging groups in the diamines and dianhydrides on reaction rates have been investigated and a possible reaction mechanism for the solution imidization processes has been proposed.
Detailed mechanistic investigations of the thermal solution imidization of polyamic acids were performed. A small amount of hydrolysis and possibly some unimolecular decomposition of amide bonds in the polyamic acid during thermal solution imidization processes were observed via combination of NMR and intrinsic viscosity measurements. However, complete "recombination" of the degraded polymer chains and their further cycloimidization could be achieved under proper imidization conditions. Potential side reactions involving intermolecular imide formation reaction were also investigated using a well characterized polyimide and also a model imide. For polyimide systems containing benzophenone tetracarboxylic acid dianhydride (BTDA), direct evidence for network formation involving imine crosslinking, was observed by high field lH-NMR spectroscopy. The gel formation was a strong function of reaction conditions, occurring under extremely dry reaction conditions and being favored at moderate reaction temperatures.
Various polyimide homo- and copolymers with controlled molecular weight and end groups were synthesized by the classic two step method and their thermal properties and solution viscosities were evaluated. Further, miscibility behavior of high performance polymer blends based upon polyimide (PI) and polybenzimidazole (PBI) was investigated. Several miscible PI/PBI blend material systems were identified, some of which showed a lower critical solution temperature (LCST), which was consistent with earlier observations. It was found that miscibility was a strong function of polarity and possible specific interactions with the polyimide components. Thus, miscibility was possible over a wide composition range with polyimides containing polar groups such as ketones, sulfones and ethers. However, immiscible blends were obtained when these polar polyimide components were replaced by non-polar groups such as the hexafluoroisopropylidene linkages.<br>Ph. D.
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Martin, Alex D. "A Convergent Approach to the Continuous Synthesis of Telmisartan via a Suzuki Reaction between Two Functionalized Benzimidazoles." VCU Scholars Compass, 2015. http://scholarscompass.vcu.edu/etd/3750.
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A direct and highly efficient synthesis has been developed for telmisartan, the active ingredient in the widely prescribed antihypertensive drug Micardis®. This approach brings together two functionalized benzimidazoles using a high-yielding Suzuki reaction that can be catalyzed by a homogeneous palladium source or palladium on a solid support.
The ability to perform the cross-coupling reaction was facilitated by the regio-controlled preparation of a 2-bromo-1-methylbenzimidazole precursor. The method developed is the first reported selective bromination at the 2-position of a benzimidazole and produces the first major precursor in high yield (93%). The second precursor, potassium (4-methyl-2-propylbenzimidazol-6-yl) trifluoroborate, was prepared from commercially available 4-bromo-2-methyl-6-nitroaniline. An optimized preparation is described that provides a direct three-step process to prepare the benzimidazole and install the borate; this synthetic sequence yields the second precursor with a 90% yield and no isolated intermediates.
The two prepared precursors were combined with a third, commercially available methyl-4’-(bromomethyl)-[1,1’-biphenyl]-2-carboxylate, utilizing a short sequence of high yielding reactions to produce the telmisartan with an 83% yield from these advanced intermediates. This new convergent approach provides the active drug ingredient with an overall yield of 74% while circumventing many issues associated with the previously reported processes. Additionally, a flow-based synthesis of telmisartan was achieved with no intermediate purifications or solvent exchanges. The continuous process utilizes a tubular reactor system coupled with a plug flow cartridge, ultimately delivering telmisartan in an 86% isolated yield.
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R, Aunós Clàudia [Verfasser], and Karl-Heinz [Akademischer Betreuer] Wiesmüller. "Synthesis and biological investigation of antifungal peptides and benzimidazoles / Clàudia R. Aunós ; Betreuer: Karl-Heinz Wiesmüller." Tübingen : Universitätsbibliothek Tübingen, 2019. http://d-nb.info/1200916190/34.
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Welsh, Athi. "Synthesis and biological evaluation of trimeric 2,5-disubstituted benzimidazoles and related trinuclear ruthenium(II) organometallic complexes." Master's thesis, Faculty of Science, 2019. https://hdl.handle.net/11427/31693.
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Cancer remains a global epidemic, with millions affected by the Non-Communicable Disease (NCD) annually. While cisplatin and its platinum(II) derivatives remain widely used chemotherapeutic agents, the undesirable side effects associated with the use of these metallodrugs and the evolution of resistance by cancers limit the scope of use of these platinum(II) complexes. Working towards addressing these issues, research has focused on the development of chemotherapeutic agents based on alternate platinum-group metals (PGMs), with ruthenium metallodrugs being among the most successful in this category. The combination of pharmacophores onto dendritic scaffolds and the combination of these scaffolds with PGMs, yielding multinuclear organometallic complexes is a strategy that has been widely used in rational drug design. However, there is limited research into multinuclear ruthenium compounds, specifically trimetallic ruthenium compounds. With this in mind, the purpose of this study was to synthesize and characterize a series of 2,5-disubstituted benzimidazole-based trimeric compounds and related trinuclear complexes bearing ruthenium(II) metal centers at the periphery. All of the synthesized compounds were screened for their in vitro cytotoxicity against the MCF-7 and MDA-MB-231 breast cancer cell lines and the 501 melanoma cell line. A series of 2,5-disubstituted benzimidazole trimeric ligands were prepared from the cyclocondensation reaction of trimeric o-phenylenediamines with either benzaldehyde or 2-pyridinecarboxaldehyde. Complexation of these 2,5-disubstituted tris-benzimidazole ligands with [RuCl(µ-Cl)(p-cymene)]2 afforded the respective trinuclear neutral CN-chelated and cationic NN-chelated ruthenium(II) complexes. In addition to this, a series of 2-ferrocenyl benzimidazole trimeric compounds were synthesized as non-planar bioisosteres of the 2-aryl 5-substituted benzimidazole trimeric ligands. All of the synthesized compounds were fully characterized using an array of spectroscopic (1H, 13C{1H}, 31P{1H} and 19F{1H} NMR, FT-IR spectroscopy) and analytical (mass spectrometry and elemental analysis) techniques. Preliminary cytotoxic screening of all of the synthesized compounds against the MCF-7 breast adenocarcinoma cell line was done. This preliminary investigation revealed that the 2-pyridyl trimeric ligands and the corresponding trinuclear cationic complexes show superior activity relative to their respective 2-phenyl trimeric ligand counterparts and the corresponding neutral cyclometallated complexes. Consequently, the 2-pyridyl tris-benzimidazole ligands and their corresponding cationic complexes were selected for cytotoxic evaluation against additional cancer cell lines (the MDA-MB-231 breast cancer and the 501mel cancer cell lines). Overall, a 2-pyridyl tris-benzimidazole ligand and two trimetallic cationic complexes showed anticancer activity either comparable or superior to that of cisplatin against the MCF-7 breast cancer cell line (IC50 ≤ 35 µM). Additionally, a 2-pyridyl trimeric benzimidazole ligand and a trimetallic cationic NN-ruthenium(II) complex showed mild activity against the MDA-MB-231 and 501mel cancer cell lines, respectively (IC50 < 35 µM in both cell lines). Selectivity studies based on the non-tumorigenic MCF-12A breast epithelial cell line indicated that selected compounds had low cytotoxicity towards non-tumorigenic cells and showed enhanced selectivity towards the MCF-7 cancerous cells relative to cisplatin. Solvent stability studies of the cationic NN-ruthenium(II) complexes show that these compounds are stable in DMSO for 48 hours under physiological conditions. Additionally, preliminary mechanistic studies of the most active complex indicate that the complex does not interact with guanosine 5’-monophosphate (5’-GMP), suggesting that this complex elicits cytotoxicity via an alternative mechanism of action.
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Nsanzubuhoro, Consolata Nsanzimpaka. "Piperazine-based pyrido[1,2-a]benzimidazoles: synthesis and pharmacological evaluation as potential antimalarial and antischistosomal agents." Master's thesis, Faculty of Science, 2018. http://hdl.handle.net/11427/30112.
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The emergence and spread of parasites resistant to first-line antimalarial drugs comprising artemisinin combination therapies (ACTs) threaten malaria control. There is therefore a need to develop novel and chemically diverse alternatives that are safe, efficacious, and able to circumvent drug resistance. Schistosomiasis is the second most prevalent tropical disease in the world after malaria, and treatment relies on a single drug: praziquantel. Although praziquantel shows multiple benefits over drugs previously used to treat schistosomiasis, dependence on it will result in therapeutic limitations and drug resistance threats. Therefore, there is a dire need to develop novel antischistosomal drugs that are effective and affordable. One attractive approach to accelerate the drug discovery and development process is the exploration of current drugs and drug leads as probable therapies for other diseases. This strategy is known as drug repurposing or drug repositioning, of which the latter is applied in this research project. The cytological similarities in the degradation of haemoglobin performed by Plasmodium parasites and Schistosoma blood flukes in malaria and schistosomiasis, respectively, suggest an opportunity for the repositioning of antimalarial scaffolds as antischistosomal agents. Pyrido[1,2-a]benzimidazoles (PBIs) demonstrate various biological and pharmacological properties such as anti-inflammatory, analgesic, antimicrobial, antiviral, and antineoplastic activities. More recently, PBI derivatives showed favourable in vitro activities against both Plasmodium falciparum and adult Schistosoma mansoni, but modest in vivo potencies. Pharmacokinetic analysis suggests that the sub-optimal in vivo efficacy of PBIs is related to solubility-limited absorption and poor metabolic stability. With the aim of circumventing these challenges, structural modifications have been employed to explore structure-activity and structure-property relationships to produce target compounds with improved druglikeness (Figure A).
This study aimed to expand the SAR by performing chemical modifications on the PBI scaffold with the purpose of maintaining or improving biological activity, and to address solubility-limited absorption challenges with this series of compounds (Figure A). The synthesized derivatives were tested against the chloroquine-sensitive (NF54) strain of P. falciparum and against adult S. mansoni concurrently. The most active compound in this PBI series, a di-fluoro-substituted derivative composed of a cyclohexyl piperazine side-chain (33), showed improved in vitro activity against the NF54 strain of P. falciparum (IC50 = 0.012 µM) and enhanced solubility (Figure A). Compounds with methylene or ethylene linkers at the R1 position (Figure A) showed comparable potency, although the directly linked phenyl piperazine analogue showed poor antiplasmodium activity. Compounds containing hydrophobic electron-withdrawing fluoro, chloro, and trifluoromethyl Craig plot substituents at the para position of the phenyl group showed enhanced antiplasmodium activity compared to those containing hydrophobic electron-releasing methyl groups and hydrophilic electron-withdrawing cyano groups. In the LHS-unsubstituted series of compounds, regio-isomerism at substituent R2 (Figure A) resulted in comparable antiplasmodium activity, and this observation was maintained with LHS-substituted PBI derivatives. Notably, unsubstituted derivatives and di-substituted groups displayed moderate to high antiplasmodium potency. Mechanistic evaluations of the compounds revealed non-existent to weak correlations between antiplasmodium activities and their potential to inhibit hemozoin (Hz) formation. This suggests that Hz inhibition is not the sole target of this class of compounds, although it may be a contributory mode of action. Compounds were also screened at 10 µM against newly transformed schistosomula and adult S. mansoni. Two compounds showed high antischistosomal activity against both larval and adult parasites, resulting in > 70% inhibition of worm viability. A turbidimetric assay was carried out to assess the solubility of target PBI compounds. In most cases, the synthesized compounds displayed high in vitro activities and slight improvements in solubility. This therefore encourages further optimization of piperazinyl PBI compounds to improve efficacy and solubility.
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Chisanga, Kelly. "Synthesis, structure-activity relationship and solubility improvement studies of potential antimalarial and antischistosomal pyrido[1,2-a]benzimidazoles." Master's thesis, Faculty of Science, 2019. http://hdl.handle.net/11427/31534.
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In 2016, 216 million malaria cases with 445,000 associated deaths were recorded according to the World Health Organization (WHO). Schistosomiasis also remains a public health issue with 207 million cases recorded globally and 280,000 deaths in the same year. Widespread emergence of parasite resistance to once-effective antimalarial options has rendered currently used drugs ineffective. Moreover, the current WHO-recommended first-line antimalarial drugs in clinical use, the artemisinin combination therapies (ACTs) are faced with the challenges of limited availability, unaffordable cost, and undesirable adverse effects. On the other hand, the treatment of schistosomiasis is severely limited to one treatment regimen, praziquantel (PQZ) which, unfortunately, has recently shown low curing rates in some parts of West Africa. Furthermore, this treatment option is far from ideal because its activity is limited to only adult schistosomes while displaying no activity towards young stages of the liver flukes. These challenges collectively provide a justification for stepping up drug discovery and development efforts aimed at identifying novel, safe and efficacious antimalarial and antischistosomal agents. Whereas, the pyrido[1,2-a]benzimidazole (PBI) scaffold is found in many pharmacologically relevant molecules including Rifaximin, an approved gastrointestinal antibacterial drug, medicinal chemistry explorations around the PBI nucleus have recently identified analogues as novel antimalarial and antischistosomal agents. Additionally, while promising antimalarial efficacy has been demonstrated in animal studies, preliminary in vitro studies of the PBI class of compounds have also demonstrated good activity against Schistosoma parasites. Recently, Mayoka reported the impressive dual antiparasitic potency of the lead compound GMP-19 (figure 1) against Plasmodium and Schistosoma parasites in vitro (IC50 = 0.430 μΜ, drug sensitive strain (NF54) and IC50 = 0.210 μΜ, adult S. mansoni, (unpublished data)). However, GMP-19 and other PBI analogues in this series of compounds, have been beset by poor solubility. Towards addressing solubility issues while retaining and improving antiparasitic activity, in this MSc dissertation, the design, synthesis, structure-activity relationship (SAR) and solubility improvement studies of PBI analogues based on the GMP-19 template are reported. In this regard, chemical modification approaches such as disruption of molecular planarity, increasing saturation, incorporating water solubilizing groups such as the polar-ionizable and the neutralpolar functionalities around the PBI nucleus were adopted. Consequently, we obtained SAR 1analogues after substituting the 4-(trifluoromethoxy)phenyl (4-OCF3Ph) moiety of GMP-19 with assorted α-methyl benzylamines. In addition, the phenyl ring on the left-hand side of the core scaffold was substituted with electron withdrawing groups such as the chloro and fluoro atoms (SAR 1.1 - 1.4), (figure 1). Although some analogues demonstrated a significant loss of antiparasitic activity (> 6.00 μM), strong submicromolar antiparasitic activity was observed with most analogues (IC50 = 0.022 -0.940 μM, PfNF54 and 30 - 69% inhibitory effect at 0.370 μM, against young forms of S. mansoni). Moreover, some analogues demonstrated poor solubility as low as < 10 μM while others showed highly improved solubility as good as 80 μM. In SAR 2.1 - 2.2, the 4-OCF3Ph and the trifluoromethyl (CF3) on the right-hand side (RHS) of the scaffold were fixed while introducing amino moieties (R) on the lipophilic phenyl ring on the left-hand side (LHS) of the PBI core (figure 2). Upon identifying the moiety with the best balance of solubility and biological activity, the 4-OCF3Ph was replaced with various acyclic amino (SAR 2.3) while the CF3 was maintained on C-3 of the core scaffold. Finally, the CF3 was replaced with the 4-CF3Ph (SAR 2.4 and 2.5) while keeping fixed the optimal basic amine and the acyclic amino moieties on the LHS, respectively. Interestingly, the pursued structural modifications delivered analogues with a wide diversity of pharmacological and physicochemical properties. While some analogues demonstrated significant loss of pharmacological activity, others exhibited potent submicromolar antiparasitic activity (IC50 < 0.012 - 0.990 μM, PfNF54 and 0.360 - 0.850 μM, adult S. mansoni). Similarly, some analogues demonstrated poor solubility as low as < 10 μM while others demonstrated improved solubility as good as 180 μM.
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Mayoka, Godfrey Wabwile. "Synthesis, pharmacological and physicochemical profiling of antimalarial and antischistosomal N-aryl 3-trifluoromethyl pyrido [1,2-α] benzimidazoles". Doctoral thesis, University of Cape Town, 2018. http://hdl.handle.net/11427/29825.
Full textAbstract:
Malaria and schistosomiasis represent the two most prevalent parasitic infections with grievous repercussions on the socio-economic development of affected countries, mainly in sub-Saharan Africa and South-East Asia. Despite their ravaging effects, the treatments of these two diseases have been committed to a limited arsenal of drugs that are threatened by resistance. This scenario, therefore, calls for decisive steps being taken towards the discovery and development of novel drugs with the ability to target multiple parasite stages and be efficacious against resistant parasite strains to achieve effective control and treatment of malaria and schistosomiasis. Originating from a World Health Organisation-Tropical Disease Research initiative, a phenotypic whole cell screening was conducted on a commercial library against Plasmodium falciparum whereupon novel hits exemplified by compound 1, embodying a pyridobenzimidazole (PBI) scaffold, were found to portray in vitro potency against both chloroquine sensitive and resistant parasites. Initial medicinal chemistry iterations generated analogues including 2 from which improved in vitro potency and demonstrable in vivo efficacy in a mouse model were observed. In this thesis, further structural diversity around the PBI motif 3 (Figure 1) was pursued with the aim of generating analogues for structure-activity and structure-property relationship studies. Beyond the asexual blood stage activity, the library of compounds generated was also evaluated for activity against the liver and gametocyte stages of Plasmodium. In exploring the probable mechanism of antimalarial action based on their planar morphology and existence of basic centres, the compounds were evaluated for their capacity to disrupt the heme detoxification process, a recognised druggable target in antimalarial drug discovery. Prioritised compounds, based on in vitro potency, were progressed for in vitro drug metabolism and pharmacokinetics assessment, including metabolic stability and cytotoxicity against Chinese hamster ovarian cell lines. Representative compounds were evaluated for their interaction potential with the human ether-a-go-go-related gene (hERG), a potassium ion channel whose inhibition can cause potentially fatal irregular heartbeats due to perturbed repolarisation of the myocardial action potential. In vivo proof-of-concept efficacy and pharmacokinetics studies were carried out on the most promising leads according to a predetermined screening cascade. Arising from this work, structure-activity relationship (SAR) trends were discernible with electron withdrawing substituents on the aromatic side appendage providing active analogues compared to compounds comprising hydrophilic electron-releasing or donating substituents. Following in vitro microsomal metabolic stability analysis, the series displayed moderate to good metabolic stability with compounds incorporating heteroaromatic side groups showing increased susceptibility to biotransformation usually arising from the aromatic ring. In a P. berghei mouse model at an oral dose of 50mg/kg over four consecutive days, two compounds 1j/GMP-19 and 4i/GMP-75 achieved 98% and 99.9% reduction in parasitaemia and led to mean survival days of 12 and 14, respectively, compared to the untreated infected mice which survived for only 6 days. A drug repositioning approach was pursued, exploiting the cellular and biological similarities in the haemoglobin degradation pathways existent in both Plasmodium parasites and schistosomes. Out of the 57 analogues tested, 12 were found to be potent inhibitors of the adult worms (IC50 ≤ 2 µM), with several compounds also displaying potency against the newly transformed schistosomula. Structural features consistent with good antischistosomal potency, interestingly, overlapped with those present in some compounds that also showed good antiplasmodial activity. Prioritised compounds subjected to in vivo efficacy studies in mice infected with schistosomes identified 1b/GMP-09, 1j/GMP-19 and 4i/GMP-75 with modest antischistosomal activity (55- 70% total worm reduction). Metabolic stability and physicochemical properties correlated with observed in vivo efficacy and solubility- limited absorption was implicated to contribute to low in vivo exposure of the compounds. Further profiling of physicochemical parameters revealed the interdependence of the properties and that crystallinity, as measured by the melting point, influenced compound solubility. In summary, the work pursued in this thesis has unravelled the structural features compatible with potent antimalarial and antischistosomal activities of N-aryl substituted 3- trifluoromethyl PBI derivatives. Additionally, structure-property trends of generated analogues have been delineated. The evolvable nature of the structure-activity and structureproperty relationship trends make these compounds appealing as candidates for further optimisation campaigns to impart improvements in physicochemical properties and drug metabolism and pharmacokinetics attributes without abrogating activity. Moreover, having identified the overlap as well as divergence in chemical spaces relating to antimalarial and antischistosomal potencies of these series inspire further investigations into the mechanisms of observed antiparasitic actions. Finally, that this work has identified targets which are panactive across multiple stages of both Plasmodium and schistosomes, and possessing favourable safety profiles, provide an exciting opportunity for pursuing these analogues as antimalarial and antischistosomal leads with the potential for malaria chemoprevention and transmission blocking.
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Tran, Minh Quan. "Méthodologie de synthèse d'imidazoles et de benzimidazoles. Approche de synthèse de la benzosceptrine et évaluation biologique." Thesis, Université Paris-Saclay (ComUE), 2015. http://www.theses.fr/2015SACLS068/document.
Full textAbstract:
Méthodologie d'addition-cyclisation de guanidines et amidines sur les quinones pour la synthèse de 2-aminobenzimidazole. Application de cette stratégie à la synthèse de benzo-bis-2-aminoimmidazole, un motif important de la benzosceptrine.Valorisation de produits synthétisés par évaluation biologique : l'inhibition de kinase, la cytotoxicité sur les lignées cellulaires cancéreuses du sang<br>Methodology of addition-cyclization of guanidines and amidines on quinones for the synthesis of 2-amino-benzimidazole. Applying this strategy to the synthesis of benzo-bis-2-aminoimmidazole, an analogue of benzosceptrine.Reclamation of products synthesized by biological evaluation: inhibition of kinase, cytotoxicity on cancer cell lines of blood
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Ndubi, Ferdinand Wafula. "Synthesis, pharmacological and solubility evaluation of antiplasmodial pyrido[1,2-a]benzimidazoles with cyclic and functionalized amine side chain substituents." Master's thesis, University of Cape Town, 2016. http://hdl.handle.net/11427/22739.
Full textAbstract:
Malaria continues to cause significant morbidity and mortality globally, especially in sub-Saharan Africa where the disease is endemic. Widespread resistance by Plasmodium parasites to chloroquine and sulphadoxine-pyrimethamine, once mainstays of malaria treatment, has further set back control efforts. Recent reports of emerging resistance to ACTs, the current first-line antimalarial drugs, present an even grimmer picture in regard to future control and eradication of malaria. Moreover, antimalarial medications in current clinical use are fraught with challenges of high cost, low availability and undesirable adverse effects associated with their use. This cocktail of factors calls for accelerated research efforts to identify novel, safe and efficacious agents for treatment of malaria. Pyrido[1,2-a]benzimidazoles (PBIs) have previously been shown to possess potent antiplasmodial activity, but their in vivo antimalarial activity is limited by poor oral bioavailability arising from low aqueous solubility. The mechanism of action of PBI antimalarials remains unknown. In an attempt to address these initial limitations associated with PBIs, and shed light on potential contributing mechanisms of action, PBI analogues containing aliphatic cyclic and functionalized amine side chain substituents bearing polar, hydrogen-bonding groups were synthesized and evaluated for pharmacological and beta-hematin inhibition activity. The functionalized and cyclic amine side chain substituents were envisaged to improve aqueous solubility of the new analogues while maintaining or improving antiplasmodial activity and metabolic stability. Aminopiperidine-based compounds were found to possess the most potent antiplasmodial and beta-hematin inhibition activity coupled with moderate to high turbidimetric solubility. Analogues with pyrrolidine and piperazine groups showed only moderate activity in the in vitro assays, and also showed lower solubility compared to the piperidines. Azetidine and cyclohexylamine substitution led to compounds with moderate to poor in vitro activity and solubility. Substitution with highly polar functions and reduced basicity of the second amino group on the cyclic amine moiety were found to be detrimental to both activity and solubility. Minimal substitution on the PBI core was also carried out, where dichloro groups were found to improve both antiplasmodial and beta-hematin inhibition activity, as well as microsomal metabolic stability. These analogues, however, showed increased cytotoxicity compared to their unsubstituted counterparts. Salt screening was also attempted for one of the frontrunner analogues, resulting in a total of five salts. All but one of the salts were moderately soluble in the kinetic solubility assay, as was the free base form of the compound. Two of the five salts showed higher solubility than the free base.
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Li, Jihui. "Copper-Catalyzed Domino C-N Bond Formation for Synthesis of N-Containing Compounds (Benzimidazoles, Imidazoles, and Guanidines) - Approach toward Total Synthesis of Natural Product Raputindoles." Thesis, Paris 11, 2013. http://www.theses.fr/2013PA112130.
Full textAbstract:
Cette thèse est constituée de trois parties : 1) Le contexte bibliographique, 2) le développement de réactions domino cupro-catalysées et 3) une approche vers la synthèse totale des raputindoles.La première partie introduit d’abord le concept de réactions domino ainsi que leurs applications, puis les réactions catalysées par du cuivre permettant de former des liaisons C-N sont passées en revue en incluant les couplages de Ullmann, Goldberg et de Chan-Lam, les séquences d’activation oxydante de liaisons C-H/formation de liaison C-N, l’insertion de nitrènes et l’hydroamination de liaisons C-C multiples. En se basant sur ces réactions élémentaires permettant de former une liaison C-N unique, les développements récents de réactions domino sont ensuite détaillés.La deuxième partie peut être subdivisée en 3 sections : 1) la synthèse de benzimidazoles, 2) la synthèse d’imidazoles and 3) la synthèse de guanidines. Un rappel des méthodes existantes pour la synthèse de ces motifs est proposé dans chaque section. Notre travail, basé sur la formation de liaisons C-N multiples selon une séquence cupro-catalysée domino, est ensuite détaillé. Celui-ci nous a permis d’aboutir au développement de voies d’accès aux benzimidazoles, en utilisant une réaction séquentielle catalysée par du cuivre en présence d’oxygène à partir d’acides boroniques et d’amidines, à la synthèse d’imidazoles par une réaction de di-amination d’alcynes vrai par des amidines et à l’obtention de guanidines et de 2-aminobenzimidines par une réaction à 3 composant. Ces réactions domino montrent une bonne efficacité et permettent d’assembler des hétérocycles à partir de précurseurs aisément accessibles.La dernière partie est consacrée à la synthèse des raputindoles. La structure, les activités et les réactions clé pour la construction de ces alcaloïdes sont discuté d’abord, nous amenant à proposer une rétrosynthèse pour accéder à ces molécules. Les réactions qui ont retenues notre attention pour construire ces molécules sont une annelation [3+2] irido-catalysée d’acides o-formylarylboronique et de 1,3-diènes, la synthèse de Leimgruber-Batcho pour obtenir des indoles et une séquence d’alkylboration-protodéboration. A partir de cela 3 stratégies ont été évaluées, montrant que l’accès à ce type de composé naturel est envisageable en combinant ces étapes<br>This thesis consists in three parts: bibliographic background, copper-catalyzed reactions for synthesis of N-containing compounds, approach to the synthesis of raputindoles.The first part introduces the domino reactions and their applications, then, copper-mediated reactions for construction of C-N bond formation are reviewed including Ullmann, Goldberg and Chan-Lam coupling, oxidative C-H activation/C-N formation, insertion of nitrenes and carbenoids, and hydroamination of multi-C-C bonds. This can be used as guides to design domino reaction. Following these copper-mediated single C-N bond formation reactions, recent developments of copper-catalyzed domino reactions for synthesis of heterocycles are described.The second part can be divided into three sections: 1) synthesis of benzimidazoles, 2) synthesis of imidazoles and 3) synthesis of guanidines. Each section summarizes the existing methods used for their synthesis. Following it, our synthetic work involving copper-catalyzed C-N bond formation domino reactions is discussed in detail. Our objectives include the synthesis of benzimidazoles through copper-catalyzed sequential reaction of benzamidines and boronic acids, synthesis of imidazoles via copper-catalyzed domino reaction of benzamidines and acetylenes, and synthesis of guanidines and 2-aminobenzimidazoles by Cu-catalyzed three-component reaction of cyanamides, boronic acids and amines. These copper-catalyzed domino reactions show high efficiencies from readily available and simple starting materials.The last part is about the total synthesis of raputindoles. The structure and bioactivities of raputindoles and key reactions for the total synthesis of raputindoles are introduced first, the synthetic strategies are then proposed on basis of relative synthetic methods. The key reactions we use for the synthesis of raputindoles are iridium catalyzed [3+2] annulation of o-formylarylboronic acids and 1,3-dienes, Leimgruber-Batcho indole synthesis, transition-metal catalyzed SN2 substitution and alkylborylation-protondeborylation. According to the three strategies we proposed, lots of relative reactions were investigated. The results show that it is possible to synthesize the raputindole molecules based on the iridium catalyzed [3+2] annulation of 2-formylarylboronic acids and 1,3-dienes
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Niemiec-Plebanek, Elzbieta. "Synthesis of small molecules targeting filovirus inhibition." Thesis, Orléans, 2014. http://www.theses.fr/2014ORLE2063.
Full textAbstract:
Les virus sont au centre de problème de santé publique. En raison de l'apparition de nouveaux virus et pour certains de leur résistance aux traitements existants il est toujours d’actualité de développement de nouveaux agents antiviraux. En général, la stratégie de lutte contre les infections virales est basée sur la vaccination ou sur l'activité des petites molécules, interférant avec un ou plusieurs processus biologiques participant au cycle de vie du virus. Dans ce contexte, nous avons conçu et synthétisé des petites bibliothèques de molécules visant des propriétés anti-filovirus. Dans ce projet de recherche, nous avons mis l'accent sur le développement de composés ciblant la protéine Niemann-Pick C1, les protéases cathepsine et le processus de réplication. Lors du développement des inhibiteurs de Neimann-Pick C1 plus de 70 composés ont été synthétisés, portant le squelette pipérazine. Afin d'obtenir des inhibiteurs de cystéine cathepsines pouvant être impliqués dans la réplication du virus Ebola, nous avons synthétisé une petite bibliothèque de composés porteurs de groupement 1,3,5-triazine et possédant des activité de l’ordre du nanomolaire sur les cathepsines B, K, L et S. Enfin, pour inhiber la réplication du virus en ciblant SAH hydrolase, nous avons proposé une série de C-nucléosides carbocyclic ayant motif de 4-aza-7,9-dideazaadenosine<br>The viruses cause the problem of public health. Due to the appearance of new viruses and their resistance to existing treatments there is still relevant to develop new antivirals. Generally, the strategy to combat viral infections is based on vaccination or on the activity of small molecules, interfering with one or more biological processes participating in virus life cycle. In this context, we took an effort to design and synthesize the library of small molecules possessing anti-filovirus properties. In this research project, we were focused on the developing of compounds targeting Niemann-Pick C1 protein, cathepsin proteases and replication process. In our effort into the development of the inhibitors of Neimann-Pick C1 we prepared the series of about 70 compounds, having in common the piperazine moiety. Diverse 1,4-N,N - substituents of piperazine, differencing in a size and shape were studied. In order to obtain efficient cysteine cathepsins inhibitors, we synthesized the small library of compounds bearing 1,3,5-triazine moiety. Finally, to inhibit the virus replication by targeting SAH hydrolase, we proposed the series of carbocyclic C-nucleosides having motif of 4-aza-7,9-dideazaadenosine
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Ferger, Richard. "Synthesis, physicochemical and biological evaluation of N-dealkylated metabolites of antimalarial pyrido[1,2-a]benzimidazoles and related compounds containing a Mannich base side-chain." Master's thesis, Faculty of Science, 2020. http://hdl.handle.net/11427/32254.
Full textAbstract:
Malaria is one of the leading causes of deaths worldwide. Despite strategic implementations aimed at decreasing mortality and morbidity rates in recent decades, this plasmodial disease continues to impact public health and the economies of developing countries. Furthermore, the emergence of resistance toward current antimalarial treatments increases the necessity for the development of novel antimalarials. The benzimidazole scaffold is an extensively researched privileged scaffold in medicinal chemistry because of its capacity to interact with numerous biological systems in various diseases, including malaria. Based on previous metabolite identification studies in liver microsomes, a new series of pyrido[1,2-a]benzimidazole (PBI) metabolites containing Mannich base side-chains were designed and synthesized. Their in vitro parasite (Plasmodium falciparum) growth and β-hematin formation inhibition activities, turbidimetric solubility, cytotoxicity, and microsomal metabolic stability in mouse liver microsomes were evaluated. To investigate structure activity relationships (SARs), the study was broadly diversified into two series (SAR-1 and SAR-2). Mannich base side-chains from SAR-1 were designed and synthesized as hypothesized N-dealkylated metabolites. In SAR-2, hypothesized N-dealkylated metabolites were compared with their respective parent compounds with a focus on modifications around the PBI core. The most potent analogues exhibited sub-micromolar activity (50% inhibitory concentration (IC50) < 1 µM) against the drug-sensitive NF54 strain of Plasmodium falciparum. Some compounds showed high activity against early- and late-stage gametocytes, the sexual stage transmissible forms of the parasite. Overall, compounds in this series were more active against early-stage gametocytes than latestage gametocytes, thus indicating stage-specificity. All but three of the analogues synthesized were potent inhibitors of β-hematin formation. Most compounds showed no cytotoxicity against HepG2 and Chinese hamster ovarian (CHO) cells. Inclusion of Mannich base side-chains influenced the in vitro microsomal metabolic stability of compounds. As expected, N-dealkylated (desethyl) metabolites showed greater metabolic stability relative to their equivalent parent compounds.
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Karim, Rehana. "Development of radical synthetic methodology using solid-phase organic synthesis." Thesis, Loughborough University, 2003. https://dspace.lboro.ac.uk/2134/34406.
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The synthesis of heterocycles using radical intermediates has become an important area of research in recent years. The aim of our research was to develop radical methodologies to construct heterocycles on solid-support. Tri-cyclic benzimidazole derivatives are desirable synthetic targets with a range of biological activity and are part of certain anti-tumour agents. Solid-supported radical reactions with substituted benzimidazoles were performed under different experimental conditions, including different solvents, three different resins (Wang, Merrifield and Rink) and different radical reagents. 4-Mercaptobenzoic acid moiety served as a traceless linker in radical ipso-substitution reactions of benzimidazole precursors attached to solid-support to construct tri-cyclic and tetracyclic benzimidazole adducts. The solution-phase radical ipso-substitution protocol was quite successfully translated onto solid-support.
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Akpinar, Hava Zekiye. "Synthesis Of Benzimidazole Containing Donor Acceptor Electrochromic Polymers." Master's thesis, METU, 2011. http://etd.lib.metu.edu.tr/upload/12613006/index.pdf.
Full textAbstract:
ABSTRACT
SYNTHESIS OF BENZIMIDAZOLE CONTAINING DONOR ACCEPTOR ELECTROCHROMIC POLYMERS
Akpinar, Hava Zekiye
M. Sc., Department of Chemistry
Supervisor: Prof. Dr. Levent Toppare
February 2011, 60 pages
Donor-acceptor-donor (DAD) type benzimidazole (BIm) and 3,4-ethylenedioxythiophene (EDOT) bearing monomers (4-(2,3-Dihydrothieno[3,4-b][1,4]dioxin-5-yl)-7-(2,3 dihydrothieno[3,4b][1,4] dioxin-7-yl)-2-benzyl-1H-benzo[d]imidazole (M1), 2,4-bis(2,3-dihydrothieno[3,4-b][1,4]dioxin-5-yl)-7-(2,3-dihydrothieno[3,4-b][1,4]dioxin-7-yl)-1H-benzo[d]imidazole (M2) and 4-(2,3-dihydrothieno[3,4-b][1,4]dioxin-5-yl)-7-(2,3-dihydrothieno[3,4-b][1,4]dioxin-7-yl)-2-ferrocenyl-1H-benzo[d]imidazole (M3)) were synthesized and electrochemically polymerized. Pendant group at 2-C position of the imidazole ring was functionalized with phenyl (P1), EDOT (P2) and ferrocene (P3) in order to observe substituent effect on electrochemical and electrochromic properties of corresponding polymers. Spectroelectrochemical results showed that different pendant groups resulted in polymers with slightly different optical band gaps (1.75, 1.69 and 1.77 eV respectively) and different number of achievable colored states. Optoelectronic performance were reported in detail.
Keywords: Benzimidazole, EDOT, Donor-Acceptor Type Polymers, Electrochromism, Conjugated Polymers.
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Howells, Ian Robert. "Synthetic studies on 1H-azepines benzimidazoles and quinoxalines." Thesis, University of Salford, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.308171.
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Ozelcaglayan, Ali Can. "Synthesis Of Electroactive Benzimidazole Derivatives And Their Electrochromic Properties." Master's thesis, METU, 2012. http://etd.lib.metu.edu.tr/upload/12615196/index.pdf.
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In order to study their electrochemical and optical properties, two donor-acceptordonor
(D-A-D) type monomers<br>4'<br>-(tert-butyl)-4,7-bis(4-hexylthiophen-2-
yl)spiro[benzo[d]imidazole-2,1'<br>-cyclohexane] (BIHT) and 4'<br>-(tert-butyl)-4,7-bis(2,3-
dihydrothieno[3,4-b][1,4]dioxin-5-yl)spiro[benzo[d]imidazole-2,1'<br>-cyclohexane]
(BIED), were electrochemically polymerized. These properties were investigated by
cyclic voltammetry and UV&ndash<br>Vis-NIR Spectroscopy techniques. Effects of different
donor groups<br>3-hexylthiophene and 3, 4-ethylenedioxythiophene (EDOT), on new
benzimidazole group, 4'<br>-(tert-butyl)spiro[benzo[d]imidazole-2,1'<br>-cyclohexane], were
investigated. These pendant groups cause slight differences in optical band gaps,
which are 1.19 eV for PBIHT, 1.15eV for PBIED. PBIHT and PBIED have both nand
p- doping. Both of them have broad absorption in the visible region. In NIR
region, both polymers revealed 46 % transmittance with high switching times.
PBIED and PBIHT showed multichromic properties. PBIED is green at neutral state.
For the most oxidized and reduced states, it is blue and red, respectively. PBIHT is
blue at neutral state, transmissive-gray in oxidized state and transmissive greenishgray
in reduced state.
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White, Wade M. "Synthesis and photoluminescent properties of linear and starburst compounds based on benzimidazole, 2-(2'-pyridyl)benzimidazole and 2,2'-dipyridylamine." Thesis, Kingston, Ont. : [s.n.], 2007. http://hdl.handle.net/1974/495.
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Carvalho, Luísa da Conceição Costa Rainho de. "Development of novel benzimidazole- based COX Inhibitors new synthetic strategies and screening of heterocyclic structures." Doctoral thesis, Faculdade de Ciencias e Tecnologia, 2014. http://hdl.handle.net/10362/13142.
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Namal, Imge. "Synthesis And Electrochemical Studies Of Fluorene And Benzimidazole Containing Conjugated Polymers." Master's thesis, METU, 2013. http://etd.lib.metu.edu.tr/upload/12615382/index.pdf.
Full textAbstract:
The synthesis and characterization of two donor acceptor type conjugated polymers were investigated.
The electrochemical properties were examined using cyclic voltammetry, spectroelectrochemistry and
kinetic studies.
The increase in the alkyl chain length attached to the fluorene unit was investigated by the
corresponding electrochemical characteristics. The synthesis was carried out via Stille coupling of 4,7-
dibromo-4'<br>-(tert-butyl)spiro[benzo[d]imidazole-2,1'<br>cyclohexane] and 2,5-
bis(tributylstannyl)thiophene with 9,9-dihexyl-9H fluorene and 9,9-didodecyl-9H fluorene
respectively. Both of the polymers were neutral state green polymers. They had optical band gaps of
2.46 and 2.54 eV respectively. Increasing the chain length resulted in an increase in solubility and
processibility of the polymer but also an increase in the band gap. This was due to the increased
bulkyness of the alkyl group, leading to a decrease in the effective conjugation and planarity. They
both had distinctive &pi<br>-&pi<br>* transitions, band structure and backbone that provides oxidative doping. P1,
with the shorter alkyl chain had a lower oxidation potential than P2. Neither of the polymers was
capable of being n-doped. They were both multichromic, revealing colors from neutral state green to
doped state blue.
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Björk, Malin. "Synthesis of sulfur and seleniumn heterocycles, including derivatives of imidazopyridine and benzimidazole /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-597-6/.
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Downey, Aaron. "Synthesis and MAO activity of a series of benzimidazolyl and indazolyl prodrugs." Thesis, Virginia Tech, 2006. http://hdl.handle.net/10919/35612.
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Parkinson's disease (PD) is a chronic, progressive disorder of the central nervous system that affects approximately 1.5 million Americans. One of the principal pathological features of PD is dopamine deficiency in the substantia nigra of the brain. A key enzyme that has been associated with the neurodegeneration seen in PD is monoamine oxidase-B (MAO-B). Several inhibitors of this enzyme have resulted in neuroprotection in the mouse model of PD. One such compound is 7-nitroindazole (1).
This thesis describes the synthesis and MAO activity of several indazolyl and benzimidazolyl prodrugs that are designed to release an enzyme inhibitor in the affected brain area. These studies have provided information regarding the nucleophilic aromatic substitutions of the ambident nucleophiles under consideration. We have also discovered a compound that releases the enzyme inhibitor upon bioactivation by MAO. These results as well as a MPTP mouse study with the aforementioned compound are detailed within.<br>Master of Science
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L'abbate, Fabrizio P. "Synthesis and investigation of benzimidazole and carbazole ß-haematin inhibiting scaffolds with antimalarial activity." Thesis, University of Cape Town, 2018. http://hdl.handle.net/11427/28432.
Full textAbstract:
Chloroquine was one of the main malarial treatments until the late 1960s when resistance began to emerge. This antimalarial targets haemozoin formation which causes a cytotoxic accumulation of free haem in the malaria parasite leading to parasite death. This is still one of the most promising pathways for treatment of the most prevalent species of malaria parasite, Plasmodium falciparum to date but, owing to growing resistance to chloroquine and other current antimalarial drugs, there is a dire need for new drugs. One strategy is to investigate non-chloroquine haemozoin inhibitors. High-throughput screening (HTS) was previously used to investigate novel β-haematin (synthetic haemozoin) inhibitors with promising P. falciparum growth inhibition activities. Of the 144 330 compounds screened, two hit compounds were selected for investigation in this project with two different scaffolds, namely benzimidazole and carbazole indole. In order to preselect benzimidazole derivatives for synthesis, Discovery Studio and Pipeline Pilot where used in tandem to enumerate 325 728 in silico compounds. These were filtered according to predicted β-haematin inhibition activities, followed by predicted malaria parasite growth activities using previously developed models based on Bayesian statistics. The predicted active compounds were further subjected to an in silico aqueous solubility model and separated according to predicted solubility values however, only 68 out of the 35 124 active compounds showed moderate solubility whilst the rest were poorly soluble. From this data, eighteen compounds were chosen for synthesis with varying functional groups. Using the same Bayesian models, biological activities for seven fragment compounds derived from the benzimidazole hit compound were predicted. Six out of seven were predicted to be β-haematin inhibitors while five out of seven were predicted active against the malaria parasite growth inhibition model. Similar Bayesian predictions were carried out on the seven proposed carbazole indole compounds with three compounds predicted to be β-haematin inhibitors while six compounds were predicted to be active against the malaria parasite growth inhibition model. The eighteen benzimidazole compounds were synthesized using a two-step synthesis, via a condensation reaction using polyphosphoric acid (PPA), 4-aminobenzoic acid and o-phenylenediamine to form the primary amine benzimidazole intermediate after which ani acylation reaction with the appropriate acid chloride furnished the desired compounds. β-haematin inhibition analysis revealed a 78% hit rate compared to the Bayesian predictions which resulted in a 24-fold enrichment compared to random screening. SAR analysis revealed an activity trend related to the position of substituents on the ring system as follows: para < ortho < meta. The type of ring system was also investigated, with a trend of phenyl < furan < pyrrole < thiophene < pyridyl found. The fragment compounds were either purchased or synthesized via standard acylation conditions using acid chlorides or acetic anhydride with primary amines as before. β-haematin inhibition analysis showed all these compounds to be inactive at the 100 µM cut-off but these compounds were still carried through to the next stage of testing in spite of these results. Molecular docking was carried out on all eighteen benzimidazole compounds in Materials Studio using the (001) and (011) β-haematin crystal faces for adsorption, together with a modified CVFF force-field. This showed a correlation between adsorption energies of the (011) β-haematin crystal face with the experimental β-haematin inhibition values. This indicated that the (011) β-haematin crystal face was the most important for β-haematin inhibition. Analysis of the benzimidazole compounds and their π-π and hydrogen bonding interactions was performed. The number of π-π interactions were found to be important for β-haematin inhibition activity. Both sets of benzimidazole compounds were tested against the NF54 chloroquine sensitive malaria parasite using growth inhibition assays with a 50% hit rate shown for the benzimidazole compounds and a 71% hit rate for the fragment study leading to a 26-fold and 36-fold enrichments compared to random screening. SAR analysis of the benzimidazole compounds revealed a trend for activity in relation to substituent position of para ≈ ortho < meta and a ring system trend of phenyl < pyridyl < thiophene < furan < pyrrole. The benzimidazole compounds were further tested against the chloroquine resistant Dd2 P. falciparum strain which showed that disubstituted compounds were more active against this strain. Cellular haem fractionation studies revealed an increase in free haem and decrease in haemozoin confirming that haemozoin inhibition is the mode of action for the benzimidazole compounds. QSAR analysis of these compounds revealed a correlation between the -Log(P. falciparum IC50) which is also known as pLog(P. falciparum IC50) and 1/βhaematin IC50, number of hydrogen bond donors and molecular depth with 1/β-haematin IC50 the most dominant term. iv The first four carbazole indole compounds were synthesized using a two-step synthesis via deprotonation of carbazole and reaction with epichlorohydrin or 1,3-dibromopropane to furnish the epoxide or alkylbromine intermediates. These intermediates underwent a further SN2 reaction using deprotonated indole to furnish four final compounds. Synthesis of another three derivatives required benzyl protection of 7-hydroxyindole alcohol first, followed by reaction with the epoxide intermediates via an SN2 mechanism to furnish the final three compounds. Analysis using the turbidimetric solubility assay revealed the best aqueous solubility range of this series of compounds to be 10-20 µM (moderately soluble). β-haematin inhibition studies were carried out on this series of compounds with a 100% hit rate found when compared to the Bayesian model data which lead to 30-fold enrichment when compared to random screening. SAR analysis showed an increase in the number of hydroxyl groups led to an increase in β-haematin inhibition activity. Docking studies were performed on these seven compounds and showed that hydrogen bonding played a role in anchoring the molecules in the binding pocket on the crystal surface with increased adsorption energies seen with an increase in the number of hydroxyl groups. Malaria parasite growth inhibition studies showed no compounds to be active against the NF54 and Dd2 strains at the 2 µM cut-off. Cellular haem fractionation studies on the carbazole indole compounds showed that this series of compounds acts via a mechanism that results in inhibition of haemoglobin uptake into the food vacuole and not via haemozoin inhibition.
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Chang, Ying-Ching, and 張孆璟. "Synthesis of Anticacer Bis (benzimidazoles) Library and Benzimidazolyl benzoxazole Related to UK-1." Thesis, 2015. http://ndltd.ncl.edu.tw/handle/8s3bfm.
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Gao, Jing-Yan, and 高敬彥. "Synthesis of benzimidazoles as antiangiogenesis agents." Thesis, 2018. http://ndltd.ncl.edu.tw/handle/99ecmt.
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Su, Yuh-Sheng, and 蘇裕勝. "Liquid-Phase Combinatorial Synthesis of Benzimidazoles." Thesis, 2003. http://ndltd.ncl.edu.tw/handle/45051713465869007110.
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Chang, Ling-Ju, and 張菱洳. "Liquid-Phase Combinatorial Synthesis of Benzimidazoles Derivative." Thesis, 2002. http://ndltd.ncl.edu.tw/handle/36944687688481446566.
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ZENG, Cian-Jhe, and 曾乾哲. "Copper-Catalyzed Synthesis of Guanidines and Benzimidazoles." Thesis, 2014. http://ndltd.ncl.edu.tw/handle/94790879466750254152.
Full textAbstract:
碩士<br>國立臺灣師範大學<br>化學系<br>102<br>This thesis contains three parts: In the first and second parts of the thesis , we
investigated the utilitzation of copper(I) iodide-catalyzed reaction of N-substituted
cyanamides to systhsize a wide variety of N,N’-disubstituted guanidine and
2-aminobenzimidazole derivatives. At the same time, In the third part, the synthetic
approach of an epigenetic DNA base 5-hydroxymethyl-2’-deoxycytidine (5-hmdC),
was studied.
In the first part, N-alkyl-N’-arylguanidines could be effectively synthesized
through the reaction of N-arylcyanamides with various primary and secondary
alkylamines, under the catalysis of copper (I) iodide and xantphos in DMF. This
methodology provides a facile access to versatile N,N’-disubstituted guanidine
derivatives from N-arylcyanamides.
In the second part, the synthesis of 2-aminobenzimidazole derivatives from the
reation of o-bromophenylcyanamides with various primary and secondary
alkylamines, under the catalysis of copper (I) iodide and 1,10-phenanthroline in
1,4-dioxane was reported. This methodology provides a direct access to
2-aminobenzimidazole derivatives. Mechanistic investigation including intermediate
studies helped establish a catalytic cycle and the regiochemistry was addressed based
on the porposed mechanism.
In the last part, sugar-protected 5-cyanocytidine was successfully prepared
from cytidine. The reduction of the 5-cyano group to form 5-hydroxymethylcytidine
achieved only in a very low yield. Although the synthesis of 5-hydroxymethylcytidine,
was accomplished, more efficient synthetic approach is yet to be developed.
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Yeh, Chih-Ming, and 葉智銘. "Liquid-Phase Combinatorial Synthesis of 2-alkylthio benzimidazoles." Thesis, 1999. http://ndltd.ncl.edu.tw/handle/31942272070127262117.
Full textAbstract:
碩士<br>國立東華大學<br>化學研究所<br>87<br>Abstract
The use of combinatorial chemistry techniques to rapidly generate large numbers of diverse small-molecule combinatorial libraries has become an accepted tool in the quest for new pharmaceutically active compounds, it has been an important tool for the synthesis of a large number of pharmaceutically interesting compounds, In couples with high capacity screening system, provide a very important strategy for generation drug leads as well as for optimizing leas compounds, this technology may revolutionize the drug discovery process.
We are focusing our research efforts on the liquid-phase combinatorial chemistry (LPCS) by the use of soluble polymer support to generate pharmaceutically interesting compounds small heterocyclic compounds, such as (2-alkylthiobenzimidazole) and benzimidazoles and Quinoxalinones libraries has be development, all reaction involved are highly efficient in giving the desired compounds in high yields and high purity just by simple precipitation and washings.
In summary, a novel liquid-phase combinatorial chemistry methods of synthesis is versatile and produces compounds with known pharmacophoric scaffolds, and which are this ideally suited for combinatorial library generation.
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Chen, Yen-Ju, and 陳彥儒. "Conjugation of Benzimidazoles with Coumarins: Their Synthesis and Conformation." Thesis, 2010. http://ndltd.ncl.edu.tw/handle/17988990404710744571.
Full textAbstract:
碩士<br>國立中央大學<br>化學研究所<br>98<br>We successfully obtained thirteen hinged benzimidazole–coumarin hybrids; these compounds were obtained by simple chemical synthesis. By studies of the spectra of nuclear magnetic resonance and infrared spectroscopy as well as the outcomes of molecular modeling, we conclude that the conformation with the thermodynamically most stable form did not contain intramolecular hydrogen bondings between the NH proton in benzimidazole and the carbonyl group in coumarin. The angle between benzimidazole and coumarin planes were 63.967°–85.705°. In the future, we will discuss the structure–activity relationship of anti-HCV, the results shall help us to understand the mechanism that the compounds for the inhibition of hepatitis C virus.
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廖本原. "(1) Synthetic Studies of Benzimidazoles from Amidoximes (2) Copper-Catalyzed Synthesis of Indoles." Thesis, 2014. http://ndltd.ncl.edu.tw/handle/04716447104067185921.
Full textAbstract:
碩士<br>國立臺灣師範大學<br>化學系<br>102<br>This thesis covers two separated topics. The first part is the synthesis of N-phenyl hetero-aryl carboxamidoximes with different substituents on the bezene ring. The reaction of the N-phenyl hetero-aryl carboxamidoximes with p-toluenesulfonic anhydride undergoes a direct intramolecular electrophilic aromatic substitution at low temperature, to afford 2-hetero-arylbenzimidazole derivatives. Moreover, we also found that the reaction of arylcarboxamidoximes with different sulfonyl reagents undergo Tiemann rearrangement reaction to afford corresponding of N,N’-disubstituted ureas.
The second part focuses on studying the synthesis of 3-cyanoindole derivatives. N-(o- ethynylphenyl)- N-tosylcyanamide derivatives were prepared from corresponding o-haloanilines or o-halobenzonitrile. 3-Cyanoindole derivatives were obtained when treatment of o-ethynylphenyl cyanamides with a catalytic amount of CuI.
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Wu, Wen-Chun, and 吳玟君. "Design and Synthesis of Diverse Pyrimidopyrroloquinoxalinediones,Metal-Assisted Synthesis of Benzimidazoles Molecular Library." Thesis, 2014. http://ndltd.ncl.edu.tw/handle/keej4j.
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Alamgir, Mahiuddin Chemistry Faculty of Science UNSW. "Synthesis and reactivity of some activated heterocyclic compounds." 2007. http://handle.unsw.edu.au/1959.4/40831.
Full textAbstract:
An alternate approach to the synthesis of calix[3]indoles has been demonstrated, but further attempted synthetic approaches to calixindoles using new leaving groups led to uncharacterized polymeric products. The synthesis of new 7,7'-diindolylmethane- 2,2'-dicarbaldehydes gives potential for further ligand design and metal complex formation. In addition, 4,6-dimethoxyindole-7- carbaldehydes have been effectively converted to a range of 6-methoxyindole-4,7-diones by Dakin oxidation. Various electrophilic substitution reactions have been performed on the 4,6-dimethoxybenzimidazoles. Formylation, acylation, acid catalyzed addition of formaldehyde and nitration revealed that the activated benzimidazoles are less reactive at the specified C-7 position compared to the analogous indoles. The key starting material for a potential calixbenzimidazole was synthesized by the selenium dioxide oxidation of 2-methyl-7-formyl-4,6-dimethoxybenzimidazole and by oxidative cleavage of 4,6-dimethoxy- 2-styrylbenzimidazole by Lemieux-Johnson reagent followed by reduction. Nevertheless, attempted preparation of calixbenzimidazole from 2-hydroxymethyl-4,6-dimethoxy benzimidazole led to formation of a dibenzimidazolyl ether. The synthesis of some novel activated bisbenzimidazoles has been developed. Furthermore, benzimidazoles were incorporated into new ligand systems which have led to a wide range of acyclic quadridentate neutral metal complexes. Activated benzimidazoles overall illustrate one electron irreversible oxidation to form a radical cation followed by multielectron oxidations. On the other hand, the nickelII and cobaltII benzimidazole metal complexes investigated showed one electron ligand centered reversible reduction. Irreversible radical cation oxidation followed by multielectron oxidation of the metal complexes further demonstrates the rich electrochemical nature of the 4,6-dimethoxybenzimidazoles. Some novel 7-(indol-2-yl)-4,6-dimethoxybenzimidazoles were prepared with indolin-2-one and triflic anhydride and an alternate procedure afforded 2-(4,6-dimethoxyindol-7-yl)-benzimidazoles from activated indoles and 2-benzimidazolinone. Two new isomeric series of 2-substituted-5,7-dimethoxybenzothiazoles and 2-substituted-4,6-dimethoxybenzothiazoles were synthesized via Jacobson cyclization. The two strategically placed electron donating methoxy groups activate these benzothiazoles to undergo various electrophilic substitutions at the 4- and 7- positions respectively.
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Garner, Matthew L. "Design, Synthesis and Study of DNA-Targeted Benzimidazole-Amino Acid Conjugates." 2013. http://hdl.handle.net/1805/3360.
Full textAbstract:
Indiana University-Purdue University Indianapolis (IUPUI)<br>The DNA minor groove continues to be an important biological target in the development of anticancer, antiviral, and antimicrobial compounds. Among agents that target the minor groove, studies of well-established benzimidazole-based DNA binders such as Hoechst 33258 have made it clear that the benzimidazole-amidine portion of these molecules promotes an efficient, site-selective DNA association. Building on the beneficial attributes of existing benzimidazole-based DNA binding agents, a series of benzimidazole-amino acid conjugates was synthesized to investigate their DNA recognition and binding properties. In this series of compounds, the benzimidazole-amidine moiety was utilized as a core DNA “anchoring” element accompanied by different amino acids to provide structural diversity that may influence DNA binding affinity and site-selectivity. Single amino acid conjugates of benzimidazole-amidines were synthesized, as well as a series of conjugates containing 20 dipeptides with the general structure Xaa-Gly. These conjugates were synthesized through a solid-phase synthetic route building from a resin-bound amino acid (or dipeptide). The synthetic steps involved: (1) the coupling of 4-formylbenzoic acid to the resin-bound amino acid (via diisopropylcarbodiimide and hydroxybenzotriazole); followed by (2) introduction of a 3,4-diaminobenzamidoxime in the presence of 1,4-benzoquinone to construct the benzimidazole ring; and, finally, (3) reduction of the resin-bound amidoxime functionality to an amidine via treatment with 1M SnCl2•2H2O in DMF before cleavage of final product from the resin. The synthetic route developed and employed was simple and straightforward except for the final reduction that proved to be very arduous. All target compounds were obtained in good yield (based upon weight), averaging 73% mono-amino acid and 78% di-amino acid final compound upon cleavage from resin. Ultimately, the DNA binding activities of the amino acid-benzimidazole-amidine conjugates were analyzed using a fluorescent intercalator displacement (FID) assay and calf thymus DNA as a substrate. The relative DNA binding affinities of both the mono- and di-amino acid-benzimidazole-amidine conjugates were generally weaker than that of netropsin and distamycin with the dipeptide conjugates showing stronger binding affinities than the mono-amino acid conjugates. The dipeptide conjugates containing amino acids with positively charged side chains, Lys-Gly-BI-(+) and Arg-Gly-BI-(+), showed the strongest DNA binding affinities amongst all our synthesized conjugates.
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CHEN, HAN-LONG, and 陳漢隆. "Studies on the synthesis and properties of lyotropic liquid crystalline polyamido-benzimidazoles." Thesis, 1991. http://ndltd.ncl.edu.tw/handle/10494003974699778058.
Full textAbstract:
碩士<br>中原大學<br>化學工程研究所<br>78<br>Benzimidazoles聚合物的合成，始於1950年，K.C.Brinker I.M.Robinson和bi-odia-
mine和脂肪族二酸(asiphatie dicarboxy acid)，首先合成了polybenaimidazoles(-
PBI), 1961年，H.Vogel 和C.S.Marvel，合成了全芳香性的PBI ，由於PBI 具有良好
的耐熱性和機械強度，使得PBI 受到眾多的矚目，目前美國太空總署(NASA)和空軍材
料室(AFML)將PBI 運用於航太工業和防御材料上，例如：複合材料，耐高溫接著劑，
防護外套等。
本研究是合成6-amino-2-(p-aminophenyl)-benzimidazole 二胺單體，和對羧酸基肉
桂酸(p-carboxylic cinnamic acid)對苯二丙烯酸(p-phenylenebisacrylic acid),
N-(p-carboxyphenyl)trimellitimide 等二酸單體，採用直接縮合法(Direct-polyc-
ondensation)合成了一系列的poly-amido-benzimidazoses 的新聚合物，其固有的黏
度值(ηinh)介於 0.5∼2.1dl/g，可溶解於一般的有機溶劑，並具有良好的機械性質
及耐熱性，本研究同時探討所合成聚合物在溶劑中的行為及液晶性。
某些聚醯胺基－苯咪在濃硫酸中當濃度達某一臨界值後，會產生異方向性和(anitro-
pic phase)，此時可在偏光顯微鏡下看到雙折射的現象，隨著濃度繼續增加，會有結
晶物析出，此結晶物的熔點在80℃左右，判斷此結晶物為結晶溶劑化物(crystallos-
olvate) 。
某些聚醯胺基－苯咪唑溶於NMP 或DMAC中，過一段時間後，溶液變為膠態，由X-ray
繞射光譜，可見到此凝膠態隨著時間的增加結晶性也增加，判斷此凝膠態為結晶溶劑
化物(crystallosolvate)。
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HSIAO, CHIEN-CHUNG, and 蕭建中. "Synthesis and Characterization of Polyimides Containing Benzimidazoles Groups for Proton Exchange Membrane." Thesis, 2019. http://ndltd.ncl.edu.tw/handle/u865vx.
Full textAbstract:
碩士<br>國立臺灣科技大學<br>化學工程系<br>107<br>A Novel diamine 3-(2-(5-aminobenzimidazolyl))aniline(m/IM/NH2), containing benzimidazole backbone was synthesized. The polyimides (PIs) were prepared by polycondensation of the diamines and Naphtha-lenetetracarboxylic dianhydride(NTDA). They had inherent viscosities in the range of 1.01~1.59 dL/g, and they could form tough and flexible films. The PIs exhibited high thermal stability with 10% decomposition temper-ature more than 530℃ in nitrogen, and their onset temperature was more than 500℃ in nitrogen. These films exhibited good mechanical properties with tensile stress around 92~135 MPa. However, the mechanical proper-ties of PIs significantly decreased when phosphoric acid doping level in-creased. This situation could be improved via crosslinking reaction of methyl group, cross-linked PIs would form close packing, and it led to decrease of phosphoric acid doping level, but it could still maintain high proton conductivity. The PIs when phosphoric acid doping level exceeded 240%, exhibited higher proton conductivity than m-PBI. For example, the proton conductivities of m6BPBI2PF1.5DMB0.5 and C5-m6BPBI2PF1.5DMB0.5 were 65.6 and 61.0 mS/cm at 160℃, respec-tively. Thus, these PIs could be the promising materials alternative to m-PBI membrane for high-temperature fuel cells applications because of their high proton conductivity and good oxidative stability.
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Yi, Shuyan. "Design and synthesis of benzimidazoles as CDK5 inhibitors and progress toward the total synthesis of tubulysin D." 2009. http://digital.library.duq.edu/u?/etd,101009.
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