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Indole-Carbohydrazide Linked Phenoxy-1,2,3-Triazole-N-Phenylacetamide Derivatives As Potent Α-Glucosidase Inhibitors: Design, Synthesis, in Vitro Α-Glucosidase Inhibition, and Computational Studies Publisher



Emadi M1 ; Mosavizadehmarvest F2 ; Asadipour A2 ; Pourshojaei Y2, 3 ; Hosseini S4 ; Mojtabavi S5 ; Faramarzi MA5 ; Larijani B6 ; Mohammadikhanaposhtani M7 ; Mahdavi M6
Authors
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Authors Affiliations
  1. 1. Electrical and Computer Engineering Department, Babol Noshirvani University of Technology, Babol, Iran
  2. 2. Department of Medicinal Chemistry, Faculty of Pharmacy & Pharmaceutics Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
  3. 3. Extremophile and Productive Microorganisms Research Center, Kerman University of Medical Sciences, Kerman, Iran
  4. 4. Shahid Beheshti University of Medical Sciences, Tehran, Iran
  5. 5. Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
  6. 6. Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
  7. 7. Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran

Source: BMC Chemistry Published:2023


Abstract

Background: A new series of indole-carbohydrazide-phenoxy-1,2,3-triazole-N-phenylacetamide hybrids 11a–o was designed based on molecular hybridization of the active pharmacophores of the potent α-glucosidase inhibitors. These compounds were synthesized and evaluated against α-glucosidase. Methods: The 15 various derivatives of indole-carbohydrazide-phenoxy-1,2,3-triazole-N-phenylacetamide scaffold were synthesized, purified, and fully characterized. These derivatives were evaluated against yeast α-glucosidase in vitro and in silico. ADMET properties of the most potent compounds were also predicted. Results: All new derivatives 11a–o (IC50 values = 6.31 ± 0.03–49.89 ± 0.09 µM) are excellent α-glucosidase inhibitors in comparison to acarbose (IC50 value = 750.0 ± 10.0 µM) that was used as a positive control. Representatively, (E)-2-(4-((4-((2-(1H-indole-2-carbonyl)hydrazono)methyl) phenoxy)methyl)-1H-1,2,3-triazol-1-yl)-N-(4-methoxyphenyl)acetamide 11d with IC50 = 6.31 µM against MCF-7 cells, was 118.8-times more potent than acarbose. This compound is an uncompetitive inhibitor against α-glucosidase and showed the lowest binding energy at the active site of this enzyme in comparison to other potent compounds. Furthermore, computational calculations predicted that compound 11d can be an orally active compound. Conclusion: According to obtained data, compound 11d can be a valuable lead compound for further structural development and assessments to obtain effective and potent new α-glucosidase inhibitors. © 2023, The Author(s).
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