Quinolinyl sulfonamides and sulphonyl esters exhibit inhibitory efficacy against New Delhi metallo--lactamase-1 (NDM-1)

The "superbug" infection caused by metallo-beta-lactamases (M beta Ls) has grown into anemergent health threat, and development of effective M beta L inhibitors to restore existing antibiotic efficacy is an ideal alternative. Although the serine-beta-lactamase inhibitors have been used in clinical settings, M beta L inhibitors are not available to date. In this work, thirty-one quinolinyl sulfonamides 1a-p and sulphonyl esters 2a-o were synthesized and assayed against M beta L NDM-1. The obtained molecules specifically inhibited NDM-1, 1a-p and 2a-o exhibited an IC50 value in the range of 0.02-1.4 and 8.3-24.8 mu M, respectively, and 1e and 1f were found to be the most potent inhibitors, with an IC50 of 0.02 mu M using meropenem (MER) as substrate. Structure-activity relationship reveals that the substitute phenyl and the phenyl with a halogen atom more significantly improve inhibitory effect of quinoline - derivatives on NDM-1. 1a-p restored antimicrobial effect of MER on E. coli with NDM-1, ECO1 and EC08, resulting in a 2-64-fold reduction in MIC values. Most importantly, le synergized MER and significantly reduced the load of ECO8 in the spleen and liver of mice after a single intraperitoneal dose. Docking studies suggested that the endocyclic nitrogen of the quinoline ring, and exocyclic nitrogen of the sulfonamide functional group are coordinate with Zn(II) ion at active sites of NDM-1. Cytotoxicity assays indicated that 1e had low cytotoxicity. This work offers potential lead compounds for further development of the clinically useful inhibitor targeting NDM-1.