Development of flavonoids derivatives as leads against Leishmaniasis and Trypanosomiasis-invited lecture

Parasites of the family of Trypanosomatidae are the agents of serious human diseases, including African sleeping sickness, Chagas' disease and leishmaniasis. There is an urgent requirement for new effective drugs since current treatments show severe side effects, develop toxicity and drug resistance. Enzymes involved in the folate cycle, e.g. dihydrofolate reductase (DHFR)-thymidylate synthase (TS) bifunctional proteins are important drug targets for the treatment of bacterial infections, cancer and certain parasitic diseases, notably malaria. Trypanosomatids are auxotrophic for folates and pterins, and the inhibition of the enzymes involved in the salvage pathways should provide effective treatments. However, antifolates are currently not yet employed in the therapy of trypanosomatids infections also because of the pteridine reductase (PTR1) activity in the target organisms. PTR is a short-chain dehydrogenase/reductase involved in the biopterin reduction pathway, able to carry out subsequent reductions of both conjugated (folate) and unconjugated (biopterin) pterins. When classical antifolate drugs inhibit DHFR-TS, PTR1 can be over-expressed ensuring the parasite survival and causing resistance to typical antifolate. The treatment of trypanosomatidic infections through the simultaneous inhibition of DHFR and PTR1 may provide a successful treatment for leishmanisis infections and Tbrucei/cruzi. Previous work in our laboratories has contributed to demonstrate this principle. Computational studies were performed to screen through a docking approach a library of 90 natural compounds from plants of different origins and target-based screening delivered flavans as one of the interesting compound class to be explored. The flavonoid structure however has been largely explored and often pleiotropic properties can be observed leading to promiscuous inhibition. The aim of the presented work is to identifiy novel chemically tractable scaffolds that will be further developed through medicinal chemistry approaches. X-ray crystallographyc structure of some of the studied compounds have been obtained and used for further structure-based drug design. While the initial compounds showed moderate detectable biological activities even related to their low solubility, recent derivatives were more soluble and showed improved enzyme inhibitory activity. The design, synthesis and biological evaluation of the flavan derivatives will be discussed. Reference 1.Ong HB et al. J Biol Chem.2011 Mar 25;286(12):10429-38. Cavazzuti A et al. PNAS. 2008 Feb 5;105(5):1448-53. 3. Ferrari S. et al, J Med Chem. 2011 Jan 13;54(1):211-21 Acknowledgement This work was supported by “PRIN 2009-2011 to MPC and NMTrypI (New medicine for Trypanosomatidic Infections) This project has received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement no.603240.