Design, synthesis, biological evaluation and in silico studies of certain aryl sulfonyl hydrazones conjugated with 1,3-diaryl pyrazoles as potent metallo-β-lactamase inhibitors
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 pneumoniae NDM-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.
Faculty of Applied Health Sciences Technology
Life Sciences, Biochemistry, Genetics, Molecular Biology, Pharmaceutical Science, Pharmacology, Toxicology
Indexed in Scopus
Indexed in Web Of Science
AIM-1, Docking, IMP-1, Inhibition assay, K. pneumonia, Liposome, MBLs, NDM-1, Pyrazoles, Sulfonyl hydrazones
Shaaban, Marwa M.; Ragab, Hanan M.; Akaji, Kenichi; McGeary, Ross P.; Bekhit, Alaa Eldin A.; Hussein, Waleed M.; Kurz, Julia L.; Elwakil, Bassma H.; Bekhit, Salma A.; Ibrahim, Tamer M.; Mahran, Mona A.; and Bekhit, Adnan A., "Design, synthesis, biological evaluation and in silico studies of certain aryl sulfonyl hydrazones conjugated with 1,3-diaryl pyrazoles as potent metallo-β-lactamase inhibitors" (2020). Faculty of Applied Health Sciences Technology. 58.