Alkyl-Resorcinol Derivatives as Inhibitors of GDP-Mannose Pyrophosphorylase with Antileishmanial Activities.

Leishmaniasis is a vector-borne disease caused by the protozoan parasite found in tropical and sub-tropical areas, affecting 12 million people around the world. Only few treatments are available against this disease and all of them present issues of toxicity and/or resistance. In this context, the development of new antileishmanial drugs specifically directed against a therapeutic target appears to be a promising strategy. The GDP-Mannose Pyrophosphorylase (GDP-MP) has been previously shown to be an attractive therapeutic target in . In this study, a chemical library of 5000 compounds was screened on both (GDP-MP) and human (GDP-MP) GDP-MPs. From this screening, oncostemonol D was found to be active on both GDP-MPs at the micromolar level. Ten alkyl-resorcinol derivatives, of which oncostemonols E and J ( and ) were described for the first time from nature, were then evaluated on both enzymes as well as on axenic and intramacrophage amastigotes. From this evaluation, compounds and inhibited both GDP-MPs at the micromolar level, and compound displayed a three-times lower IC on GDP-MP, at 11 µM, than on GDP-MP. As they displayed mild activities on the parasite, these compounds need to be further pharmacomodulated in order to improve their affinity and specificity to the target as well as their antileishmanial activity.