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Design and Synthesis of Novel Quinazolinone-Pyrazole Derivatives As Potential Α-Glucosidase Inhibitors: Structure-Activity Relationship, Molecular Modeling and Kinetic Study Publisher Pubmed



Azimi F1 ; Azizian H2 ; Najafi M3 ; Hassanzadeh F1 ; Sadeghialiabadi H1 ; Ghasemi JB4 ; Ali Faramarzi M5 ; Mojtabavi S5 ; Larijani B6 ; Saghaei L1 ; Mahdavi M6
Authors
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Authors Affiliations
  1. 1. Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Science, Isfahan University of Medical Science, Hezar Jerib, Isfahan, 817416-73461, Iran
  2. 2. Department of Medicinal Chemistry, School of Pharmacy-International Campus, Iran University of Medical Science, Tehran, Iran
  3. 3. Department of Chemistry, Isfahan University of Technology, Isfahan, 84156-83111, Iran
  4. 4. School of Chemistry, University College of Science, University of Tehran, P.O. Box 14155-6455, Tehran, Iran
  5. 5. Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O. Box 14155-6451, Tehran, 1417614411, Iran
  6. 6. Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Research Institute, Tehran University of Medical Sciences, Tehran, Iran

Source: Bioorganic Chemistry Published:2021


Abstract

In this study, a new series of quinazolinone-pyrazole hybrids were designed, synthesized and screened for their α-glucosidase inhibitory activity. The results of the in vitro screening indicated that all the molecular hybrids exhibited more inhibitory activity (IC50 values ranging from 60.5 ± 0.3 µM-186.6 ± 20 μM) in comparison to standard acarbose (IC50 = 750.0 ± 10.0 µM). Limited structure–activity relationship suggested that the variation in the inhibitory activities of the compounds affected by different substitutions on phenyl rings of diphenyl pyrazole moiety. The enzyme kinetic studies of the most potent compound 9i revealed that it inhibited α-glucosidase in a competitive mode with a Ki of 56 μM. Molecular docking study was performed to predict the putative binding interaction. As expected, all pharmacophoric moieties used in the initial structure design playing a pivotal role in the interaction with the binding site of the enzyme. In addition, by performing molecular dynamic investigation and MM-GBSA calculation, we investigated the difference in structural perturbation and dynamic behavior that is observed over α-glycosidase in complex with the most active compound and acarbose relative to unbound α-glycosidase enzyme. © 2021
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