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

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JournalMedChemComm
DatePublished - 17 Aug 2015
Issue number10
Volume6
Number of pages6
Pages (from-to)1767-1772
Original languageEnglish

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-μM anti-plasmodial activity.

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