From pan-active to parasite-selective antiparasitic agents: A scaffold hopping approach

Abstract

Vector-borne parasitic diseases (VBPDs) represent a major global public health concern, with human African trypanosomiasis (HAT), Chagas disease, leishmaniasis, and malaria collectively threatening millions of people, particularly in developing regions. Climate change may further influence their transmission and geographic spread, increasing the global burden. As drug resistance continues to rise, there is an urgent need for novel therapeutic agents to expand treatment options and limit disease progression. Exploiting a cell-based phenotypic approach, we had previously developed 1,3,4-oxadiazole derivatives, as broad-spectrum low-toxicity agents active against protozoan parasites including Plasmodium falciparum, Leishmania spp. and Trypanosoma brucei. Herein, we applied a scaffold-hopping approach to develop novel chemotypes by replacing the central 1,3,4-oxadiazole core with 1,2,4-oxadiazole and oxazole rings. A systematic investigation allowed us to generate two novel libraries of compounds and carry out extensive Structure-Activity-Relationship studies and early drug discovery pharmacological liability characterization. Starting from pan-active 1,3,4-oxadiazole-based antiparasitic agents, we identified two anti-kinetoplastid molecules bearing the 1,2,4-oxadiazole core and one promising anti-T. brucei agent featuring an oxazole core. Our work paves the way for the development of novel chemotypes to successfully fight parasitic infections.

Keywords: 1,2,4-Oxadiazole; Human African trypanosomiasis; Leishmaniasis; Malaria; Oxazole; Scaffold hopping.