Botulinum neurotoxins (BoNTs), and in particular serotype A, are the most poisonous of known
biological substances, and are responsible for the flaccid
paralysis of the disease state
botulism. Because of the extreme toxicity of these
enzymes, BoNTs are considered highest priority biothreat agents. To counter BoNT serotype A (
BoNT/A)
poisoning, the discovery and development of small molecule,
drug-like inhibitors as post-intoxication therapeutic agents has been/is being pursued. Specifically, we are focusing on inhibitors of the
BoNT/A light chain (LC) (ie, a
metalloprotease) subunit, since such compounds can enter neurons and provide post-intoxication protection of the
enzyme target substrate. To aid/facilitate this
drug development effort, a pharmacophore for inhibition of the
BoNT/A LC subunit was previously developed, and is continually being refined via the incorporation of novel and diverse inhibitor chemotypes. Here, we describe several analogs of a promising therapeutic chemotype in the context of the pharmacophore for
BoNT/A LC inhibition. Specifically, we describe: 1) the pharmacophoric 'fits' of the analogs and how these 'fits' rationalize the in vitro inhibitory potencies of the analogs and 2) pharmacophore refinement via the inclusion of new components from the most potent of the presented analogs.