Discovery and in vivo evaluation of alcohol-containing benzothiazoles as potent dual-targeting bacterial DNA supercoiling inhibitors

Abstract

A series of dual-targeting, alcohol-containing benzothiazoles has been identified with superior antibacterial activity and drug-like properties. Early lead benzothiazoles containing carboxylic acid moieties showed efficacy in a well-established in vivo model, but inferior drug-like properties demanded modifications of functionality capable of demonstrating superior efficacy. Eliminating the acid group in favor of hydrophilic alcohol moieties at C 5, as well as incorporating solubilizing groups at the C7 position of the core ring provided potent, broad-spectrum Gram-positive antibacterial activity, lower protein binding, and markedly improved efficacy in vivo. © 2014 Elsevier Ltd. All rights ..