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Design, Synthesis, and in Silico Studies of Benzimidazole Bearing Phenoxyacetamide Derivatives As Α-Glucosidase and Α-Amylase Inhibitors Publisher



Shayegan N1 ; Iraji A2, 3 ; Bakhshi N7 ; Moazzam A1 ; Faramarzi MA4 ; Mojtabavi S4 ; Pour SMM5 ; Tehrani MB8 ; Larijani B1 ; Rezaei Z1 ; Yousefi P7 ; Khoshneviszadeh M6, 7 ; Mahdavi M1
Authors
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Authors Affiliations
  1. 1. Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
  2. 2. Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
  3. 3. Central Research Laboratory, Shiraz University of Medical Sciences, Shiraz, Iran
  4. 4. Department of Pharmaceutical Biotechnology, Faculty of Pharmacy and Biotechnology Research Center, Tehran University of Medical Sciences, Tehran, Iran
  5. 5. Liosa Pharmed Parseh Company, Shiraz, Iran
  6. 6. Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
  7. 7. Department of Medicinal Chemistry, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
  8. 8. Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

Source: Journal of Molecular Structure Published:2022


Abstract

Benzimidazole bearing phenoxyacetamide derivatives 7a-l were designed and synthesized as anti-diabetic agents. All derivatives were evaluated for in vitro α-glucosidase and α-amylase inhibition. Compounds 7a-l exhibited a varying degree of α-glucosidase inhibitory activity with IC50 values between 99.6 ± 3.1 - >750 µM compared with standard acarbose (IC50 = 750.0 ± 5.6 µM). Structure-activity relationships showed the important role of methoxy substituent on phenoxy linker to improve the potency. Also, the substitution of 4-F (7j) and 4-Cl (7k) moiety at the Y position improved the inhibitory activity. Enzyme kinetic studies of compound 7j proved that their inhibition was the competitive type with a Ki value of 67.0 µM. The results of α-amylase inhibitory activities indicated that most of the synthesized derivatives had moderate to weak inhibitory activities against α-amylase. Among them, compounds 7c (X = H; Y = 2-Br) and 7j (X = OMe; Y = 4-F) showed the strongest inhibition with 50.0% and 45.0% inhibition at 108 µM. Molecular docking studies were performed to understand the binding interaction of the compounds. © 2022 Elsevier B.V.
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