Dottorato in MOLECULAR DESIGN AND CHARACTERIZATION FOR THE
PROMOTION OF HEALTH AND WELL-BEING: FROM DRUG TO FOOD

Titolo della tesi: Nitrogen-Rich Heterocycles in Drug Discovery

Throughout my three years as a PhD student, I have worked on several projects, mostly concerning research and development of new microtubules active compounds, aimed to the cancer and trypanosomiasis treatment. The wider project concerned the development of a new chemotherapy agent as inhibitor of tubulin polymerization. My research group has significant experience in this field, so we decided to continue this study focusing on the need to overcome problems such as drug resistance, and poor bioavailability. Starting from derivates previously reported, we evaluated the nitrogen role to affect potency and pharmaceutical proprieties, as the water solubility. Thus, we synthesized a new 3-aroyl-1-aryl pyrrole compound which showed significant activity mainly in a lymphoma model, both in vitro and in vivo. Then, further studies of our research group highlighted as the 3-aroyl-1,4-aryl derivates were more promising for additional optimization and we decided to evaluate the tubulin inhibition and the anticancer activity of these new congeners. These inhibitors showed a good efficiency on brain tumors such as glioblastoma. Also, considering that many traditional drugs fail to effectively cross epithelial and cellular barriers, which reduces their effectiveness and requires high dosages, the new compounds had instead a better pharmacokinetic profile, proving to be able to cross the blood-brain barrier. Another aim of my PhD project was to search for new targets for cancer therapy. A widespread problem is the poor selectivity of the classic chemotherapeutic compounds, which are able to inhibit the proliferation of cancer cells but show certain degree cytotoxicity also towards normal cells. Anticancer therapy is, therefore, increasingly focused on new specific cancer targets. In this context we have developed new inhibitors of β-catenin. During my visiting PhD period at University of California, San Diego, my research focused on the development on new microtubules stabilizing compounds aimed to treat the human african trypanosomiasis. Since, the current therapy for this disease show limitations in term of efficacy, toxicity and administration, a new treatment is strongly needed. Starting from previous studies, we design and synthesized new triazolopirimidines with the final goal to improve the selectivity against T. brucei. Finally, I also took part in two smaller projects in the antiviral field. Starting from docking studies we developed possible antiviral agents active against Norovirus.