SYNTHESIS OF ANTIFUNGAL COMPOUNDS

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.