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

被引：21
|
作者：
Shaaban, Marwa M. [1 ]
Ragab, Hanan M. [1 ]
Akaji, Kenichi [2 ]
McGeary, Ross P. [3 ]
Bekhit, Alaa-Eldin A. [4 ]
Hussein, Waleed M. [3 ,5 ]
Kurz, Julia L. [3 ]
Elwakil, Bassma H. [6 ]
Bekhit, Salma A. [7 ]
Ibrahim, Tamer M. [8 ]
Mahran, Mona A. [1 ]
Bekhit, Adnan A. [1 ,9 ,10 ]
机构：
[1] Alexandria Univ, Dept Pharmaceut Chem, Fac Pharm, Alexandria 21521, Egypt
[2] Kyoto Pharmaceut Univ, Dept Med Chem, Kyoto, Japan
[3] Univ Queensland, Sch Chem & Mol Biosci, Brisbane, Qld 4072, Australia
[4] Univ Otago, Food Sci, Dunedin, New Zealand
[5] Helwan Univ, Dept Pharmaceut Organ Chem, Fac Pharm, Helwan, Egypt
[6] Pharos Univ, Fac Allied Med Sci, Dept Med Lab Technol, Alexandria, Egypt
[7] Alexandria Univ, High Inst Publ Hlth, Alexandria 21568, Egypt
[8] Kafrelsheikh Univ, Dept Pharmaceut Chem, Fac Pharm, Kafrelsheikh 33516, Egypt
[9] Alexandria Univ, Canc Nanotechnol Res Lab CNRL, Fac Pharm, Alexandria 21521, Egypt
[10] Univ Bahrain, Allied Hlth Dept, Coll Hlth & Sport Sci, Pharm Program, POB 32038, Zallaq, Bahrain
来源：
BIOORGANIC CHEMISTRY | 2020年 / 105卷
关键词：
Sulfonyl hydrazones; Pyrazoles; MBLs; NDM-1; IMP-1; AIM-1; K; pneumonia; Inhibition assay; Liposome; Docking; PSEUDOMONAS-AERUGINOSA; CRYSTAL-STRUCTURE; DERIVATIVES; PNEUMONIA; OPTIMIZATION; MEROPENEM; LIPOSOMES; INSIGHTS; REVEALS; BINDING;
D O I：
10.1016/j.bioorg.2020.104386
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
Based on a structure-guided approach, aryl sulfonyl hydrazones conjugated with 1,3-diaryl pyrazoles were designed to target metallo-beta-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 mu M) 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.
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页数：11
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