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.

Synthesis of 1,4,6-Tricarbonyl Compounds via Regioselective Gold(I)-Catalyzed Alkyne Hydration and Their Application in the Synthesis of α-Arylidene-butyrolactones.

We report a direct, straightforward, and regioselective hydration of 1,4-enynes designed from Morita-Baylis-Hillman adducts. Under smooth conditions and short reaction times, gold-catalyzed hydration of internal alkynes provides synthetically useful ketones as single regioisomers in yields higher than 90%. The synthetic usefulness of this protocol was demonstrated by the conversion of selected ketones into biologically valuable α-alkylidene-γ-lactones upon reduction with sodium borohydride. In the course of the scope evaluation, we discovered that this methodology could also furnish α-arylidene-ß,γ-butenolides.