Discovery of pyridyl-based inhibitors of Plasmodium falciparum N-myristoyltransferaseMore about Open Access at the Crick
Authors listZY Yu JA Brannigan K Rangachari WP Heal AJ Wilkinson Anthony Holder RJ Leatherbarrow EW Tate
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-mu M anti-plasmodial activity.
Issue number 10