Structural modification of pantothenamides counteracts degradation by pantetheinase and improves antiplasmodial activity

Pantothenamides are secondary or tertiary amides of pantothenic acid, the vitamin precursor of the essential cofactor and universal acyl carrier coenzyme A. A recent study has demonstrated that pantothenamides inhibit the growth of blood-stage Plasmodium falciparum with submicromolar potency by exerting an effect on pantothenic acid utilization, but only when the pantetheinase present in the growth medium has been inactivated. Here, we demonstrate that small modifications of the pantothenamide core structure are sufficient to counteract pantetheinase-mediated degradation and that the resulting pantothenamide analogues still inhibit the in vitro proliferation of P. falciparum by targeting a pantothenic acid-dependent process (or processes). Finally, we investigated the toxicity of the most potent analogues to human cells and show that the selectivity ratio exceeds 100 in one case. Taken together, these results provide further support for pantothenic acid utilization being a viable target for antimalarial drug discovery.