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Synthesis, Molecular Dynamic, and in Silico Study of New Ethyl 4-Arylpyrimido[1,2-B]Indazole-2-Carboxylate: Potential Inhibitors of Α-Glucosidase Publisher



Gashghaee M1 ; Azizian H2 ; Adib M1 ; Mohammadikhanaposhtani M3 ; Mojtabavi S4 ; Faramarzi MA4 ; Rezaei Y5 ; Biglar M6 ; Larijani B6 ; Rastegar H7 ; Mahdavi M6
Authors
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Authors Affiliations
  1. 1. School of Chemistry, College of Science, University of Tehran, PO Box 14155-6455, Tehran, Iran
  2. 2. Department of Medicinal Chemistry, School of Pharmacy, Iran University of Medical Sciences, Tehran, Iran
  3. 3. Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
  4. 4. Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
  5. 5. Vice- Chancellery Food and Drug, Bushehr University Of Medical Sciences, Bushehr, Iran
  6. 6. Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
  7. 7. Cosmetic products research center, Iranian food and drug administration, MOHE, Tehran, Iran

Source: Journal of Molecular Structure Published:2022


Abstract

A new series of ethyl 4-arylpyrimido[1,2-b]indazole-2-carboxylate derivatives 7a-p were synthesized and screened for their α-glucosidase inhibitory activity. The half of these new compounds displayed inhibitory activity against α-glucosidase, with IC50 values in the range of 66.98 ± 0.05–650.30 ± 0.08 µM as compared to acarbose as standard inhibitor with IC50 value of 762.59 ± 0.04 µM. Among the title compounds, compound 7n presented the most inhibition effect against α-glucosidase. Kinetic study revealed that compound 7n is a competitive inhibitor with a Ki value of 66 µM. 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-glucosidase in complex with the most active compound and acarbose relative to unbound α-glucosidase enzyme. © 2022
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