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

Danish Shahzad; Aamer Saeed; Fayaz Ali Larik; Pervaiz Ali Channar; Qamar Abbas; Mohamed F Alajmi; M Ifzan Arshad; Mauricio F Erben; Mubashir Hassan; Hussain Raza; Sung-Yum Seo; Hesham R El-Seedi

doi:10.3390/molecules24081511

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

Molecules. 2019 Apr 17;24(8):1511. doi: 10.3390/molecules24081511.

Authors

Affiliations

¹ Department of Chemistry, Quaid-I-Azam University, Islamabad 45320, Pakistan. [email protected].
² Department of Chemistry, Quaid-I-Azam University, Islamabad 45320, Pakistan. [email protected].
³ Department of Chemistry, Quaid-I-Azam University, Islamabad 45320, Pakistan. [email protected].
⁴ Department of Chemistry, Quaid-I-Azam University, Islamabad 45320, Pakistan. [email protected].
⁵ Department of Physiology, University of Sindh, Jamshoro 76080, Pakistan. [email protected].
⁶ Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia. [email protected].
⁷ Department of Chemistry, Quaid-I-Azam University, Islamabad 45320, Pakistan. [email protected].
⁸ 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. [email protected].
⁹ Department of Biological Sciences, College of Natural Sciences, Kongju National University, 56 Gongjudehak-Ro, Gongju, Chungnam 32588, Korea. [email protected].
¹⁰ Department of Biological Sciences, College of Natural Sciences, Kongju National University, 56 Gongjudehak-Ro, Gongju, Chungnam 32588, Korea. [email protected].
¹¹ Department of Biological Sciences, College of Natural Sciences, Kongju National University, 56 Gongjudehak-Ro, Gongju, Chungnam 32588, Korea. [email protected].
¹² Pharmacognosy Group, Department of Medicinal Chemistry, Biomedical Center (BMC), Uppsala University, SE-751 23 Uppsala, Sweden. [email protected].

Abstract

A series of symmetrical salicylaldehyde-bishydrazine azo molecules, 5a-5h, 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.

Keywords: SAR; antioxidant; bis-azo Schiff bases; chemo-informatics; dual inhibitor; kinetic mechanism; molecular docking; α-amylase; α-glucosidase inhibitor.

Publication types

Evaluation Study

MeSH terms

Animals
Glycoside Hydrolase Inhibitors* / chemical synthesis
Glycoside Hydrolase Inhibitors* / chemistry
Molecular Docking Simulation*
Molecular Structure
Swine
alpha-Amylases / antagonists & inhibitors*
alpha-Amylases / chemistry*
alpha-Glucosidases / chemistry*

Substances

Glycoside Hydrolase Inhibitors
alpha-Amylases
alpha-Glucosidases