Discovery and Hit-to-Lead Optimization of Benzothiazole Scaffold-Based DNA Gyrase Inhibitors with Potent Activity against <i>Acinetobacter baumannii</i> and <i>Pseudomonas aeruginosa</i>

Abstract

We have developed compounds with a promising activity against <i>Acinetobacter baumannii</i> and <i>Pseudomonas aeruginosa</i>, which are both on the WHO priority list of antibiotic-resistant bacteria. Starting from DNA gyrase inhibitor <b>1</b>, we identified compound <b>27</b>, featuring a 10-fold improved aqueous solubility, a 10-fold improved inhibition of topoisomerase IV from <i>A. baumannii</i> and <i>P. aeruginosa</i>, a 10-fold decreased inhibition of human topoisomerase IIα, and no cross-resistance to novobiocin. Cocrystal structures of <b>1</b> in complex with <i>Escherichia coli</i> GyrB24 and (<i>S</i>)-<b>27</b> in complex with <i>A. baumannii</i> GyrB23 and <i>P. aeruginosa</i> GyrB24 revealed their binding to the ATP-binding pocket of the GyrB subunit. In further optimization steps, solubility, plasma free fraction, and other ADME properties of <b>27</b> were improved by fine-tuning of lipophilicity. In particular, analogs of <b>27</b> with retained anti-Gram-negative activity and improved plasma free fraction were identified. The series was found to be nongenotoxic, nonmutagenic, devoid of mitochondrial toxicity, and possessed no ion channel liabilities.