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Discovery of pyridyl-based inhibitors of Plasmodium falciparum N-myristoyltransferase.

ABSTRACT: N-Myristoyltransferase (NMT) represents an attractive drug target in parasitic infections such as malaria due to its genetic essentiality and amenability to inhibition by drug-like small molecules. Scaffold simplification from previously reported inhibitors containing bicyclic cores identified phenyl derivative 3, providing a versatile platform to study the effects of substitution on the scaffold, which yielded pyridyl 19. This molecule exhibited improved enzyme and cellular potency, and reduced lipophilicity compared to inhibitor 3. Further structure-based inhibitor design led to the discovery of 30, the most potent inhibitor in this series, which showed single-digit nM enzyme affinity and sub-?M anti-plasmodial activity.

SUBMITTER: Yu Z

PROVIDER: S-EPMC4757856 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Discovery of pyridyl-based inhibitors of Plasmodium falciparum N-myristoyltransferase.

Yu Zhiyong Z Brannigan James A JA Rangachari Kaveri K Heal William P WP Wilkinson Anthony J AJ Holder Anthony A AA Leatherbarrow Robin J RJ Tate Edward W EW

MedChemComm 20150819 10

N-Myristoyltransferase (NMT) represents an attractive drug target in parasitic infections such as malaria due to its genetic essentiality and amenability to inhibition by drug-like small molecules. Scaffold simplification from previously reported inhibitors containing bicyclic cores identified phenyl derivative 3, providing a versatile platform to study the effects of substitution on the scaffold, which yielded pyridyl 19. This molecule exhibited improved enzyme and cellular ...[more]

PMID: 26962430

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