Specific Stereoisomeric Conformations Determine the Drug Potency of Cladosporin Scaffold against Malarial Parasite

The dependence of drug potency on
diastereomeric configurations is a key facet. Using a novel general
divergent synthetic route for a three-chiral center antimalarial natural
product cladosporin, we built its complete library of stereoisomers
(cladologs) and assessed their inhibitory potential using parasite-,
enzyme-, and structure-based assays. We show that potency is manifest
via tetrahyropyran ring conformations that are housed in the ribose
binding pocket of parasite lysyl tRNA synthetase (KRS). Strikingly,
drug potency between top and worst enantiomers varied 500-fold, and
structures of KRS-cladolog complexes reveal that alterations at C3
and C10 are detrimental to drug potency whereas changes at C3 are
sensed by rotameric flipping of glutamate 332. Given that scores of
antimalarial and anti-infective drugs contain chiral centers, this
work provides a new foundation for focusing on inhibitor stereochemistry
as a facet of antimicrobial drug development.