Synthesis and biological evaluation of 2-substituted heterocyclic quinolones as inhibitors of Vibrio cholerae sodium pumping NADH-ubiquinone oxidoreductase (NQR).

The rise of multi-drug-resistant bacteria highlights the need for antibiotics that act through novel mechanisms of action. The Na+-pumping NADH-Ubiquinone (UQ) oxidoreductase (NQR) is a respiratory enzyme foundin many pathogenic bacteria including Vibrio cholerae and plays a central role in energy production and redox balance. This enzyme is essential to the virulence of V. cholerae and structural motifs that are unique to NQR are not found in the humans, making it an excellent target for antibiotic drug design. Herein we report the synthesis and biological evaluation of 2-substituted heterocyclic quinolones designed to target the ubiquinone binding site of NQR. The most potent quinolone derivative exhibits 45% inhibition at 50 μM and docking studies indicate that it overlaps with the surrogate ubiquinone substrate within the binding pocket. These compounds also show inhibition of NQR while maintaining low toxicity in mammalian HeLa and HFF-1 cells, expanding the chemical space of bacterial respiratory enzyme inhibitors and supporting their development as a potential class of bacteriostatic antibiotics.