Divergent Modes of Enzyme Inhibition in a Homologous Structure-Activity Series

A (locking screen identified reversible, noncovalent inhibitors (e.g., I) of the parasite cysteine protease cruzain. Chemical optimization of I led to a series of oxadiazoles possessing interpretable SAR and potencies as much as 500-fold greater than 1. Detailed investigation of the SAR series subsequently revealed that many members of the oxadiazole class (and surprisingly also 1) act via divergent modes of inhibition (competitive or via colloidal aggregation) depending oil the assay conditions employed.