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Novel C-2 Symmetric Molecules as α-Glucosidase and α-Amylase Inhibitors: Design, Synthesis, Kinetic Evaluation, Molecular Docking and Pharmacokinetics

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Department of Chemistry, Quaid-I-Azam University, Islamabad 45320, Pakistan
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Department of Physiology, University of Sindh, Jamshoro 76080, Pakistan
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Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
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CEQUINOR (UNLP, CONICET-CCT La Plata), Departamento de Química, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, Boulevard 120 e/60 y 64 N°1465, La Plata 1900, Argentina
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Department of Biological Sciences, College of Natural Sciences, Kongju National University, 56 Gongjudehak-Ro, Gongju, Chungnam 32588, Korea
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Pharmacognosy Group, Department of Medicinal Chemistry, Biomedical Center (BMC), Uppsala University, SE-751 23 Uppsala, Sweden
*
Author to whom correspondence should be addressed.
Molecules 2019, 24(8), 1511; https://doi.org/10.3390/molecules24081511
Received: 8 March 2019 / Revised: 27 March 2019 / Accepted: 2 April 2019 / Published: 17 April 2019
(This article belongs to the Section Bioorganic Chemistry)
A series of symmetrical salicylaldehyde-bishydrazine azo molecules, 5a5h, have been synthesized, characterized by 1H-NMR and 13C-NMR, and evaluated for their in vitro α-glucosidase and α-amylase inhibitory activities. All the synthesized compounds efficiently inhibited both enzymes. Compound 5g was the most potent derivative in the series, and powerfully inhibited both α-glucosidase and α-amylase. The IC50 of 5g against α-glucosidase was 0.35917 ± 0.0189 µM (standard acarbose IC50 = 6.109 ± 0.329 µM), and the IC50 value of 5g against α-amylase was 0.4379 ± 0.0423 µM (standard acarbose IC50 = 33.178 ± 2.392 µM). The Lineweaver-Burk plot indicated that compound 5g is a competitive inhibitor of α-glucosidase. The binding interactions of the most active analogues were confirmed through molecular docking studies. Docking studies showed that 5g interacts with the residues Trp690, Asp548, Arg425, and Glu426, which form hydrogen bonds to 5g with distances of 2.05, 2.20, 2.10 and 2.18 Å, respectively. All compounds showed high mutagenic and tumorigenic behaviors, and only 5e showed irritant properties. In addition, all the derivatives showed good antioxidant activities. The pharmacokinetic evaluation also revealed promising results View Full-Text
Keywords: bis-azo Schiff bases; dual inhibitor; α-glucosidase inhibitor; α-amylase; antioxidant; SAR; chemo-informatics; kinetic mechanism; molecular docking bis-azo Schiff bases; dual inhibitor; α-glucosidase inhibitor; α-amylase; antioxidant; SAR; chemo-informatics; kinetic mechanism; molecular docking
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Shahzad, D.; Saeed, A.; Larik, F.A.; Channar, P.A.; Abbas, Q.; Alajmi, M.F.; Arshad, M.I.; Erben, M.F.; Hassan, M.; Raza, H.; Seo, S.-Y.; El-Seedi, H.R. Novel C-2 Symmetric Molecules as α-Glucosidase and α-Amylase Inhibitors: Design, Synthesis, Kinetic Evaluation, Molecular Docking and Pharmacokinetics. Molecules 2019, 24, 1511.

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