Synthesis of new indazole based dual inhibitors of α-glucosidase and α-amylase enzymes, their in vitro, in silico and kinetics studies

Rafaila Rafique; Khalid Mohammed Khan; Arshia; Kanwal; Sridevi Chigurupati; Abdul Wadood; Ashfaq Ur Rehman; Arunkumar Karunanidhi; Shehryar Hameed; Muhammad Taha; Mariya Al-Rashida

doi:10.1016/j.bioorg.2019.103195

Synthesis of new indazole based dual inhibitors of α-glucosidase and α-amylase enzymes, their in vitro, in silico and kinetics studies

Bioorg Chem. 2020 Jan:94:103195. doi: 10.1016/j.bioorg.2019.103195. Epub 2019 Aug 23.

Authors

Affiliations

¹ H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
² H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan; Department of Clinical Pharmacy, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, P.O. Box 31441, Dammam, Saudi Arabia. Electronic address: [email protected].
³ Department of Pharmacology, Faculty of Pharmacy, Qassim University, Buraidah 52571, Saudi Arabia.
⁴ Department of Biochemistry, Shankar Campus, Abdul Wali Khan University, Mardan, Khyber Pukhtoonkhwa, Pakistan.
⁵ Department of Medical Microbiology and Parasitology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia.
⁶ Department of Clinical Pharmacy, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, P.O. Box 31441, Dammam, Saudi Arabia.
⁷ Department of Chemistry, Forman Christian College (A Chartered University), Lahore, Pakistan.

PMID: 31451297
DOI: 10.1016/j.bioorg.2019.103195

Abstract

The current study describes the discovery of novel inhibitors of α-glucosidase and α-amylase enzymes. For that purpose, new hybrid analogs of N-hydrazinecarbothioamide substituted indazoles 4-18 were synthesized and fully characterized by EI-MS, FAB-MS, HRFAB-MS, ¹H-, and ¹³C NMR spectroscopic techniques. Stereochemistry of the imine double bond was established by NOESY measurements. All derivatives 4-18 with their intermediates 1-3, were evaluated for in vitro α-glucosidase and α-amylase enzyme inhibition. It is worth mentioning that all synthetic compounds showed good inhibition potential in the range of 1.54 ± 0.02-4.89 ± 0.02 µM for α-glucosidase and for α-amylase 1.42 ± 0.04-4.5 ± 0.18 µM in comparison with the standard acarbose (IC₅₀ value of 1.36 ± 0.01 µM). In silico studies were carried out to rationalize the mode of binding interaction of ligands with the active site of enzymes. Moreover, enzyme inhibitory kinetic characterization was also performed to understand the mechanism of enzyme inhibition.

Keywords: Carbothioamide; Hyperglycemia; Indazole; α-amylase; α-glucosidase.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Computer Simulation
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology
Glycoside Hydrolase Inhibitors / chemical synthesis*
Glycoside Hydrolase Inhibitors / chemistry
Glycoside Hydrolase Inhibitors / pharmacology
In Vitro Techniques
Indazoles / chemistry*
Kinetics
Magnetic Resonance Spectroscopy
Molecular Docking Simulation
Molecular Structure
Structure-Activity Relationship
alpha-Amylases / antagonists & inhibitors*

Substances

Enzyme Inhibitors
Glycoside Hydrolase Inhibitors
Indazoles
alpha-Amylases