Development of Potent 3-Br-isoxazoline-Based Antimalarial and Antileishmanial Compounds.

Starting from the structure of previously reported 3-Br-isoxazoline-based covalent inhibitors of glyceraldehyde 3-phosphate dehydrogenase, and with the intent to improve their metabolic stability and antimalarial activity, we designed and synthesized a series of simplified analogues that are characterized by the insertion of the oxadiazole ring as a bioisosteric replacement for the metabolically labile ester/amide function. We then further replaced the oxadiazole ring with a series of five-membered heterocycles and finally combined the most promising structural features. All the new derivatives were tested in vitro for antimalarial as well as antileishmanial activity.