Discovery of substituted oxadiazoles as a novel scaffold for DNA gyrase inhibitors

Abstract

DNA gyrase and topoisomerase IV are type IIa topoisomerases that are essential bacterial enzymes required to oversee the topological state of DNA during transcription and replication processes. Their ATPase domains, GyrB and ParE, respectively, are recognized as viable targets for small molecule inhibitors, however, no synthetic or natural product GyrB/ParE inhibitors have so far reached the clinic for use as novel antibacterial agents, except for novobiocin which was withdrawn from the market. In the present study, a series of substituted oxadiazoles have been designed and synthesized as potential DNA gyrase inhibitors. Structure-based optimization resulted in the identification of compound 35, displaying an IC₅₀ of 1.2 μM for Escherichia coli DNA gyrase, while also exhibiting a balanced low micromolar inhibition of E. coli topoisomerase IV and of the respective Staphylococcus aureus homologues. The most promising inhibitors identified from each series were ultimately evaluated against selected Gram-positive and Gram-negative bacterial strains, of which compound 35 inhibited Enterococcus faecalis with a MIC₉₀ of 75 μM. Our study thus provides further insight into the structural requirements of substituted oxadiazoles for dual inhibition of DNA gyrase and topoisomerase IV.

Keywords: 1,2,4-Oxadiazoles; Antibacterial screening; Computer-aided drug design; DNA gyrase inhibition; Topoisomerase IV inhibition.