Exploring heteroaromatic rings as a replacement for the labile amide of antiplasmodial pantothenamides

ABSTRACTThe Plasmodium parasites that cause malaria are adept at developing resistance to antimalarial drugs, necessitating the search for new antiplasmodials. Although several amide analogs of pantothenate (pantothenamides) show potent antiplasmodial activity, hydrolysis by pantetheinases (or vanins) present in blood rapidly inactivates them. We report herein the facile synthesis and biological activity of a small library of pantothenamide analogs in which the labile amide group is replaced with a variety of heteroaromatic rings. Several of the new analogs display antiplasmodial activity in the nanomolar range against P. falciparum and/or P. knowlesi in the presence of pantetheinase. A previously reported triazole and an isoxazole derivative presented here were further characterized and found to possess high selectivity indices, medium or high Caco-2 permeability, and medium or low microsomal clearance in vitro. Although we show here that the two compounds fail to suppress proliferation of P. berghei in vivo, pharmacokinetic and contact time data presented provide a benchmark for the compound profile required to achieve antiplasmodial activity in mice and should facilitate lead optimization.

A chiral-at-metal asymmetric catalyzed vinylogous Michael addition of ortho-methyl aromatic nitro compounds for isoxazole derivative synthesis

A chiral-at-metal rhodium(iii) complex catalyzed asymmetric vinylogous Michael addition of 5-methyl 4-nitroisoxazoles with α,β-unsaturated 2-acyl imidazoles has been developed, delivering the corresponding adducts with up to 96% yield and 97% ee.