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.
Highlights
A parasitic disease in humans primarily caused by Plasmodium falciparum (Pf) and Plasmodium vivax (Pv), was responsible for about 584 000 deaths in 2013, mainly of pregnant women and children living in Africa.[1]
In order to interpret the effect of substitution on the scaffold, inhibitors derived from phenyl (18), 4-chloro phenyl (22) and 3-pyridyl (19) were selected for crystallographic studies and co-crystal structures with a
Scaffold reduction from our earlier PfNMT inhibitors containing bicyclic cores to phenyl-based inhibitors provided a flexible platform to study the effect of scaffold and substituent variations, allowing the discovery of pyridyl as an attractive core, the superiority of which was later explained by structural studies
Summary
A parasitic disease in humans primarily caused by Plasmodium falciparum (Pf) and Plasmodium vivax (Pv), was responsible for about 584 000 deaths in 2013, mainly of pregnant women and children living in Africa.[1]. Following the discovery that single-ring scaffolds displayed good affinity against Leishmania donovani NMT,[29] disubstituted (ortho- and meta-) phenyl rings were selected as analogues of the structures of previously reported inhibitors 1 and 2,27,28 and linked through an ester or its bioisosteric oxadiazole to a terminal benzyl substituent (Fig. 1).
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