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Synthesis, in Vitro and in Silico Screening of 2-Amino-4-Aryl-6-(Phenylthio) Pyridine-3,5-Dicarbonitriles As Novel Α-Glucosidase Inhibitors Publisher Pubmed



Ali M1 ; Khan KM1, 2, 3 ; Mahdavi M4 ; Jabbar A5 ; Shamim S1 ; Salar U6 ; Taha M3 ; Perveen S7 ; Larijani B4 ; Faramarzi MA8
Authors
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Authors Affiliations
  1. 1. H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan
  2. 2. Pakistan Academy of Sciences, 3-Constitution Avenue G-5/2, Islamabad, Pakistan
  3. 3. Department of Clinical Pharmacy, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, P.O. Box 31441, Dammam, Saudi Arabia
  4. 4. Endocrinology & Metabolism Research Institute (EMRI), Tehran University of Medical Sciences, Tehran, Iran
  5. 5. Department of Veterinary Biosciences, Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, 250 Princes Highway, Werribee, 3030, Victoria, Australia
  6. 6. Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan
  7. 7. PCSIR Laboratories Complex, Karachi, Shahrah-e-Dr. Salimuzzaman Siddiqui, Karachi, 75280, Pakistan
  8. 8. Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

Source: Bioorganic Chemistry Published:2020


Abstract

Inhibition of α-glucosidase enzyme is of prime importance for the treatment of diabetes mellitus (DM). Apart of many organic scaffolds, pyridine based compounds have previously been reported for wide range of bioactivities. The current study reports a series of pyridine based synthetic analogues for their α-glucosidase inhibitory potential assessed by in vitro, kinetics and in silico studies. For this purpose, 2-amino-4-aryl-6-(phenylthio)pyridine-3,5-dicarbonitriles 1–28 were synthesized and subjected to in vitro screening. Several analogs, including 1–3, 7, 9, 11–14, and 16 showed many folds increased inhibitory potential in comparison to the standard acarbose (IC50 = 750 ± 10 µM). Interestingly, compound 7 (IC50 = 55.6 ± 0.3 µM) exhibited thirteen-folds greater inhibition strength than the standard acarbose. Kinetic studies on most potent molecule 7 revealed a competitive type inhibitory mechanism. In silico studies have been performed to examine the binding mode of ligand (compound 7) with the active site residues of α-glucosidase enzyme. © 2020 Elsevier Inc.
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