Multitargeted inhibition of key enzymes associated with diabetes and Alzheimer's disease by 1,3,4‐oxadiazole derivatives: Synthesis, in vitro screening, and computational studies

Author:

Fatima Bibi1,Saleem Faiza1,Salar Uzma2,Chigurupati Sridevi3,Felemban Shatha G.4,Ul‐Haq Zaheer2,Tariq Syeda S.2,Almahmoud Suliman A.3,Taha Muhammad5,Shah Syed T. A.6,Khan Khalid M.1ORCID

Affiliation:

1. H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences University of Karachi Karachi Pakistan

2. Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences University of Karachi Karachi Pakistan

3. Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy Qassim University Buraidah Saudi Arabia

4. Department of Medical Laboratory Science Fakeeh College for Medical Sciences Jeddah Saudi Arabia

5. Department of Clinical Pharmacy Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University Dammam Saudi Arabia

6. Department of Education Sukkur IBA University Sukkur Pakistan

Abstract

AbstractA library of 22 derivatives of 1,3,4‐oxadiazole‐2‐thiol was synthesized, structurally characterized, and assessed for its potential to inhibit α‐amylase, α‐glucosidase, acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and antioxidant activities. Most of the tested compounds demonstrated good to moderate inhibition potential; however, their activity was lower than that of the standard acarbose. Significantly, compound 3f exhibited the highest inhibition potential against α‐glucosidase and α‐amylase enzymes, with IC50 values of 18.52 ± 0.09 and 20.25 ± 1.05 µM, respectively, in comparison to the standard acarbose (12.29 ± 0.26; 15.98 ± 0.14 µM). Compounds also demonstrated varying degrees of inhibitory potential against AChE (IC50 = 9.25 ± 0.19 to 36.15 ± 0.12 µM) and BChE (IC50 = 10.06 ± 0.43 to 35.13 ± 0.12 µM) enzymes compared to the standard donepezil (IC50 = 2.01 ± 0.12; 3.12 ± 0.06 µM), as well as DPPH (IC50 = 20.98 ± 0.06 to 52.83 ± 0.12 µM) and ABTS radical scavenging activities (IC50 = 22.29 ± 0.18 to 47.98 ± 0.03 µM) in comparison to the standard ascorbic acid (IC50 = 18.12 ± 0.15; 19.19 ± 0.72). The kinetic investigations have demonstrated that the compounds exhibit competitive‐type inhibition for α‐amylase, noncompetitive‐type inhibition for α‐glucosidase and AChE, and mixed‐type inhibition for BChE. Additionally, a molecular docking study was performed on all synthetic oxadiazoles to explore the interaction details of these compounds with the active sites of the enzymes.

Publisher

Wiley

Subject

Drug Discovery,Pharmaceutical Science

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