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

Abstract

The 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.

Exploring Heteroaromatic Rings as a Replacement for the Labile Amide of Antiplasmodial Pantothenamides

“…a longer substituent to compensate), compared to the isoxazole. Similar to what was previously reported for triazole pantothenamide analogs, 21 alkyl chains are preferred over the phenethyl group associated with high potency in unmodified pantothenamides, 5 with phenethyl analogs 3h and 3m…”

“…to modify pantothenamides to protect them from pantetheinase-mediated hydrolysis. 9,[12][13][15][16][17][18][19][20][21] Such alterations have been reported at the secondary hydroxyl group, 17,20 the geminal-dimethyl group, 15,17,19 the -alanine moiety, 9,16,18 and the labile amide itself, [12][13]21 sometimes at the cost of activity. Our team has reported a series of analogs in which the labile amide group is replaced with a 1,2,3-triazole ring that translates into enhanced stability and potency.…”

“…Our team has reported a series of analogs in which the labile amide group is replaced with a 1,2,3-triazole ring that translates into enhanced stability and potency. 21 Our previous exploration of structure-activity relationships (SARs) focused on the triazole N-substituent, the length of the carbon linker between the pantoyl group and the triazole ring, and the relative position of the two substituents on the ring. It was found that the triazole 1,4-substitution pattern with a simple methylene linker between the triazole and pantoyl moieties is preferred for optimal antiplasmodial activity, and yields compounds with low nanomolar antiplasmodial activity, e.g.…”

“…1 and 2, which are proposed to mimic compounds with an inverted amide group (Figure 1). 12,21 We report herein the synthesis and antiplasmodial activity of novel pantothenamide analogs containing diverse heteroaromatic rings instead of the labile amide moiety, several of which show similar potency to triazole compound 1. In addition, we report selectivity indices, time-of-kill, Caco-2 cell permeability, metabolic stability, and the first in vivo evaluation, of heteroaromatic ring-modified pantothenamides.…”

Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183

“…knowlesi (38). The importance of combining MMV693183 with a partner drug is highlighted by the possibility of generating resistance against this compound that can also be transmitted to the mosquito vector.…”