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A pantetheinase-resistant pantothenamide with potent, on-target, and selective antiplasmodial activity.


ABSTRACT: Pantothenamides inhibit blood-stage Plasmodium falciparum with potencies (50% inhibitory concentration [IC50], ?20 nM) similar to that of chloroquine. They target processes dependent on pantothenate, a precursor of the essential metabolic cofactor coenzyme A. However, their antiplasmodial activity is reduced due to degradation by serum pantetheinase. Minor modification of the pantothenamide structure led to the identification of ?-methyl-N-phenethyl-pantothenamide, a pantothenamide resistant to degradation, with excellent antiplasmodial activity (IC50, 52 ± 6 nM), target specificity, and low toxicity.

SUBMITTER: Macuamule CJ 

PROVIDER: S-EPMC4432145 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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A pantetheinase-resistant pantothenamide with potent, on-target, and selective antiplasmodial activity.

Macuamule Cristiano J CJ   Tjhin Erick T ET   Jana Collins E CE   Barnard Leanne L   Koekemoer Lizbé L   de Villiers Marianne M   Saliba Kevin J KJ   Strauss Erick E  

Antimicrobial agents and chemotherapy 20150406 6


Pantothenamides inhibit blood-stage Plasmodium falciparum with potencies (50% inhibitory concentration [IC50], ∼20 nM) similar to that of chloroquine. They target processes dependent on pantothenate, a precursor of the essential metabolic cofactor coenzyme A. However, their antiplasmodial activity is reduced due to degradation by serum pantetheinase. Minor modification of the pantothenamide structure led to the identification of α-methyl-N-phenethyl-pantothenamide, a pantothenamide resistant to  ...[more]

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