Design of new α-glucosidase inhibitors based on the bis-4-hydroxycoumarin skeleton: Synthesis, evaluation, and in silico studies.

Autor: Soleimani Z; Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran., Mohammadi M; Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran., Halimi M; Department of Biology, Babol Branch, Islamic Azad University, Babol, Iran., Safapoor S; Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran., Dastyafteh N; Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran., Safaie E; Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran., Mojtabavi S; Department of Pharmaceutical Biotechnology, Faculty of Pharmacy and Biotechnology Research Center, Tehran University of Medical Sciences, Tehran, Iran., Faramarzi MA; Department of Pharmaceutical Biotechnology, Faculty of Pharmacy and Biotechnology Research Center, Tehran University of Medical Sciences, Tehran, Iran., Bozorgi-Koushalshahi M; Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran., Larijani B; Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran., Mohammadi-Khanaposhtani M; Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran. maryammoha@gmail.com., Mahdavi M; Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran. momahdavi@tums.ac.ir.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2024 Aug 12; Vol. 14 (1), pp. 18693. Date of Electronic Publication: 2024 Aug 12.
DOI: 10.1038/s41598-024-69592-0
Abstrakt: In this work, we have reported the design, synthesis, in vitro, and in silico enzymatic evaluation of new bis-4-hydroxycoumarin-based phenoxy-1,2,3-triazole-N-phenylacetamide derivatives 5a-m as potent α-glucosidase inhibitors. All the synthesized analogues showed high inhibition effects against α-glucosidase (IC 50 values ranging between 6.0 ± 0.2 and 85.4 ± 2.3 µM) as compared to the positive control acarbose (IC 50  = 750.0 ± 0.6 µM). Among the newly synthesized compounds 5a-m, 2,4-dichloro-N-phenylacetamide derivative 5i with inhibition effect around 125-folds more than the acarbose was identified as the most potent entry. A structure-activity relationship (SAR) study about the title compounds 5a-m demonstrated that the inhibition effects of these compounds depend on the pattern of substitution on the N-phenylacetamide ring. The interaction modes and binding energies in the active site of enzyme of the important analogues (in term of SAR study) were evaluated through molecular docking study. Molecular dynamics and prediction of pharmacokinetic properties and toxicity of the most potent compound 5i also evaluated and the obtained data was compared with the acarbose.
(© 2024. The Author(s).)
Databáze: MEDLINE
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