Synthesis, Biological Evaluation, and Computational Analysis of 1,4-Naphthoquinone Derivatives as Inhibitors of the Sodium-Dependent NADH:Ubiquinone Oxidoreductase (NQR) in Vibrio cholerae.

The therapeutic efficacy of antibiotics has been significant in extending human life expectancy by combating virulent bacterial infections. Nevertheless, multidrug-resistant (MDR) microorganisms remain a global crisis as these bacteria have developed resistance to conventional antibacterial agents. An unexplored antibiotic target found exclusively in bacteria is the Na+-translocating NADH:ubiquinone oxidoreductase (NQR), which is an indispensable membrane-bound bacterial enzyme complex that enables cellular functionality and is present in many infectious bacterial species, including Vibrio cholerae and H. influenzae. NQR serves as an essential complex in the bacterial electron transport chain (ETC) and operates as a highly conserved primary Na+ pump that drives many bioenergetic functions. This six-subunit protein shuttles electrons from NADH to ubiquinone, which drives the translocation of Na+ ions and creates a gradient that provides the driving force for various cellular processes. We have synthesized and evaluated a series of 1,4-naphthoquinones that exhibit high potency against NQR with minimal cytotoxicity and potential to serve as new, NQR-targeting antibacterial agents for use against V. cholerae.