Discovery of highly potent and selective antiparasitic new oxadiazole and hydroxy-oxindole small molecule hybrids

A series of highly active hybrids were discovered as novel antiparasitic agents. Two heterocyclic scaffolds (1,2,4-oxadiazole and 3-hydroxy-2-oxindole) were linked, and the resulting compounds showed in vitro activities against intracellular amastigotes of two protozoan parasites, Trypanosoma cruzi and Leishmania infantum. Their cytotoxicity was assessed using HFF-1 fibroblasts and HepG2 hepatocytes. Compounds 5b, 5d, 8h and 8o showed selectivity against L. infantum (IC50 values of 3.89, 2.38, 2.50 and 2.85 μM, respectively). Compounds 4c, 4q, 8a and 8k were the most potent against T. cruzi, exhibiting IC50 values of 6.20, 2.20, 2.30 and 2.20 μM, respectively. Additionally, the most potent anti-T. cruzi compounds showed in vitro efficacies comparable or superior to that of benznidazole. These easy-to-synthesize molecules represent novel chemotypes for the design of potent and selective lead compounds for Chagas disease and leishmaniasis drug discovery. [Display omitted] •49 compounds having a new heterocyclic arrangement were synthesized in only one step using a Morita-Baylis-Hillman reaction and fully characterized.•The new compounds were evaluated in vitro against intracellular amastigotes of two protozoan parasites, Trypanosoma cruzi and Leishmania infantum. Their cytotoxicity was assessed using HFF-1 fibroblasts and HepG2 hepatocytes.•Compounds 5b, 5d, 8h and 8o showed selectivity against L. infantum exhibiting IC50 values of 3.89, 2.38, 2.50 and 2.85 μM, respectively.•Compounds 4c, 4q, 8a and 8k were the most potent against T. cruzi, exhibiting IC50 values of 6.20, 2.20, 2.30 and 2.20 μM, respectively. The most potent anti-T. cruzi compounds showed in vitro efficacies comparable or superior to that of benznidazole.•These new compounds represent novel chemotypes for the design of potent and selective lead compounds for Chagas disease and leishmaniasis drug discovery.