Auswahl der wissenschaftlichen Literatur zum Thema „Amidinourea compounds“

Current therapy against herpes simplex viruses (HSV) relies on the use of a few nucleoside antivirals such as acyclovir, famciclovir and valacyclovir. However, the current drugs are ineffective against latent and drug-resistant HSV infections. A series of amidinourea compounds, designed as analogues of the antiviral drug moroxydine, has been synthesized and evaluated as potential non-nucleoside anti-HSV agents. Three compounds showed micromolar activity against HSV-1 and low cytotoxicity, turning to be promising candidates for future optimization. Preliminary mode of action studies revealed that the new compounds act in an early stage of the HSV replication cycle, just after the viral attachment and the entry phase of the infection.

A series of substituted 3-chlorophenylpiperazinone derivatives were synthesised using L-778123 (an imidazole-containing FTase inhibitor) as a model by bioisosteric replacement of the imidazole ring. The final compounds were evaluated against two human cancer cell lines including A549 (lung cancer) and HT-29 (colon cancer) by MTT assay. The results showed that substitution of imidazole ring with 1-amidinourea, semicarbazide, and thiobiuret led to improvement of cytotoxic activity against both cell lines.

Systemic fungal infections represent a threat to public health, and annually more than 150 million people suffer from fungal diseases. This worrisome data reflects the growing group of patients with immunocompromised conditions: due to cancer chemotherapy, organ transplanting or affected by AIDS, and the outbreaks of azoles resistant strains. Moreover, the global emergency caused by SARS-CoV-2 led to long term hospitalizations, and intubation increased the susceptibility to developing fungal infections. Therefore, now more than ever, the challenge of developing new antifungal drugs is dramatically urgent. Our research group has been interested in the great potential of guanylated compounds as new antifungal agents since 2007. During these 15 years, three series of derivatives, characterized by an amidinoureas scaffold, have been developed. The structure of these compounds is new and not shared with other antifungal drugs present on the market. Consequently, they show remarkably antifungal activity, especially among Candida strains resistant to azole drugs. The first chapter of my thesis deals with synthesizing new antifungal compounds with a macrocyclic amidinourea scaffold. Firstly, a novel compound, BM37, was synthesized through a convergent approach using the ring-closing metathesis (RCM)as a key step. Secondly, we decided to conduct advanced biological investigations of our lead compound, BM1. Consequently, we face the need to prepare this compound on a gram scale. To achieve this result, we changed the synthetic route and took inspiration from Fukuyama’s work designing a new strategy to obtain 1 gram of BM1. The second chapter of my thesis explores the design and synthesis of novel inhibitors targeting human chitinases. This project started when we investigated a putative target for the amidinoureas compounds endowed with antifungal activity. This research led us to the Chitinase family. In particular, our interest fell on human chitinases due to their involvement in chronic inflammatory lung diseases. The development of new human chitinase inhibitors, characterized by two different chemical scaffolds, is the aim of this second chapter. The former was the macrocyclic amidinoureas scaffold. Here three derivatives: BM56, BM57 and BM58, were synthesized and evaluated on human chitinases. The latter explored the chemical space related to the 6-piperazine-1-ylpyrazine-2-carboxamide, a new scaffold that emerged from a structure-based virtual screening. In this case, we synthesized a small, focused library of derivatives. The third chapter of my thesis describes my work as visiting PhD student at Uppsala University. During this period, I have been involved in the alkylation of the N position of 3-methyl indole with several cyclic ketones using a green and efficient amide coupling reagent, the TP3®. Finally, the last chapter contains chemical and biological data of all the compounds presented in the thesis.

Le infezioni fungine sistemiche sono, oggigiorno, di importanza cruciale per pazienti affetti da AIDS, che hanno subito trapianti d’organo, o che stanno subendo chemio/radioterapia contro un tumore, situazioni in cui il sistema immunitario può essere debilitato al punto di non riuscire a gestirle. Le infezioni virali, per esempio, rappresentano un altro caso in cui il sistema immunitario è indebolito, fatto che può portare allo sviluppo di infezioni fungine latenti. Un altro importante aspetto correlato alla terapia antifungina è lo sviluppo della resistenza che, insieme al fatto che esistono in commercio poche classi di antifungini, rende la ricerca in questo campo molto importante e di interesse globale. Negli ultimi anni, il nostro gruppo di ricerca ha esplorato il grande potenziale di composti guanilati naturali e di sintesi, un lavoro articolato che ha portato allo sviluppo di nuovi composti macrociclici e non-azolici, che mostrano attività antifungina. In questa tesi, questa classe di composti è stata studiata attraverso la sintesi sia di nuovi membri della famiglia sia di membri già noti che hanno subito un’intensa caratterizzazione biologica. Durante la ricerca di un target per questi composti, il campo d’azione di queste amidinouree macrocicliche è stato allargato, poiché hanno dimostrato di possedere attività anti-chitinasi. Siccome la chitinasi si è dimostrata un argomento molto studiato di recente, visto il suo coinvolgimento in molte patologie umane di tipo infiammatorio, abbiamo disegnato in modo razionale e investigato nuovi derivati macrociclici da usare come inibitori della human acidic mammalian chitinase, esplorando le grandi possibilità di questo scaffold particolare. Il primo capitolo di questa tesi tratta il lavoro svolto sui nuovi derivati riguardanti il progetto antifungini, la loro attività biologica e uno studio dettagliato sul composto di riferimento. Il secondo capitolo, invece, si focalizza sulla Chitinasi, la sua identificazione, il suo coinvolgimento nelle malattie umane e i nostri sforzi volti alla comprensione di come inibire la sua attività attraverso la sintesi dei primi derivati di questa serie correlata di composti. Il terzo capitolo, infine, riporta le procedure chimiche e biologiche utilizzate.
Systemic fungal infections are, nowadays, of crucial importance for patients affected by AIDS, that have been transplanted, or that are subjected to chemio/radiotherapy for tumors, situations that the immune system may result unable to manage. Viral infections, as an example, often weaken the immune system, leading to the emergence of latent fungal infections. Another important problem related to the antifungal therapy is the onset of resistance that, along with the fact that very few new classes of antifungals have been discovered, makes the research in this field of great importance and interest worldwide. In the last decade, our group explored the great potential of natural and synthetic guanylated compounds, a great amount of work that led to the development of new non-azole antifungal compounds with a macrocycle, endowed with antifungal activity. In this thesis, this class of compounds has been investigated even more, through the synthesis of both novel members of the family and already known ones, which underwent a deep biological characterization. During the search for a putative target for these compounds, the scope of the macrocyclic amidinoureas has been widened, because they showed anti-chitinase activity. Since Chitinases resulted to be a hot topic recently, because of their involvement in many human inflammatory pathologies, we rationally designed and investigated macrocyclic derivatives as human acidic mammalian chitinase inhibitors, exploring the possibilities of this peculiar scaffold. The first chapter of this thesis deals with the novel derivatives for the antifungal project, their biological activity and with an in-depth study of the lead compound. The second chapter, instead, focuses on the Chitinase, its identification, its involvement in human diseases and our efforts to understand how to inhibit its activity via the synthesis of the first derivatives of this related series of compounds. In the third chapter, finally, the chemical and biological procedures have been reported.