Tetrazole-based inhibitors of the bacterial enzyme N-succinyl-l,l-2,6-diaminopimelic acid desuccinylase as potential antibiotics

Abstract

Based on a hit from a high-throughput screen, a series of phenyltetrazole amides was synthesized and assayed for inhibitory potency against DapE from Haemophilus influenzae (HiDapE). The inhibitory potency was modest but confirmed, with the most potent analog containing an aminothiazole moiety displaying an IC50 = 50.2 ± 5.0 μM. Docking reveals a potential binding mode wherein the amide carbonyl bridges both zinc atoms in the active site, and the tetrazole forms key hydrogen bonds with Arg330.