Abstract
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•New conjugates of aryl sulfonyl hydrazone and 1,3-diaryl pyrazole were designed and synthesized.•They showed promising inhibition against NDM-1, IMP-1 and AIM-1 MBLs.•They exhibited promising ex vivo antibacterial activity against resistant clinical isolates of K. pneumoniae.•They were able to re-sensitize resistant K. pneumoniae (K5) towards meropenem and cefalexin.•The docking experiments on NDM-1 and IMP-1 rationalized the observed in vitro MBLs inhibition activity.
Based on a structure-guided approach, aryl sulfonyl hydrazones conjugated with 1,3-diaryl pyrazoles were designed to target metallo-β-lactamases (MBLs), using Klebsiella pneumoniaeNDM-1 as a model. The in vitro MBLs inhibition showed remarkable inhibition constant for most of the designed compounds at a low micromolar range (1.5–16.4 µM) against NDM-1, IMP-1 and AIM-1 MBLs. Furthermore, all compounds showed promising antibacterial activity against (K+, K1-K9) resistant clinical isolates of K. pneumoniae and were able to re-sensitize resistant K. pneumoniae (K5) strain towards meropenem and cefalexin. Besides, in vivo toxicity testing exhibited that the most active compound was non-toxic and well tolerated by the experimental animals orally up to 350 mg/kg and up to 125 mg/kg parenterally. The docking experiments on NDM-1 and IMP-1 rationalized the observed in vitro MBLs inhibition activity. Generally, this work presents a fruitful matrix to extend the chemical space for MBLs inhibition. This aids in tackling drug-resistance issues in antibacterial treatment.