Design, synthesis and evaluation of novel LpxC inhibitors containing a hydrazone moiety as Gram-negative antibacterial agents

Abstract

LpxC inhibitors are new-type antibacterial agents developed in the last twenty years, mainly against Gram-negative bacteria infections. To enable the development of novel LpxC inhibitors with potent antibacterial activities, several series of compounds were designed and synthesized and their antibacterial activities were evaluated against E. coli ATCC25922, P. aeruginosa ATCC27853, P. aeruginosa clinical isolate PAE 22-1, K. pneumoniae ATCC700603, K. pneumoniae clinical isolate KPN⁺22-1 in vitro. Compound 6i exhibited significant antibacterial activities against above five Gram-negative bacteria except P. aeruginosa ATCC27853. Moreover, compound 6i exhibited moderate liver microsomal stability and a promising pharmacokinetic profile (AUC_0-t = 1050 ng h mL⁻¹, oral bioavailability of 13.3 %) in Sprague-Dawley rats, acceptable PPB, low risk of drug-drug interactions and non-cytotoxic activity against hepatic cell. Collectively, compound 6i could be a promising Gram-negative antibacterial agent for further investigation.