Synthesis and screening of (E)-3-(2-benzylidenehydrazinyl)-5,6-diphenyl-1,2,4-triazine analogs as novel dual inhibitors of α-amylase and α-glucosidase

Shahbaz Shamim; Khalid Mohammed Khan; Nisar Ullah; Sridevi Chigurupati; Abdul Wadood; Ashfaq Ur Rehman; Muhammad Ali; Uzma Salar; Ahmad Alhowail; Muhammad Taha; Shahnaz Perveen

doi:10.1016/j.bioorg.2020.103979

Synthesis and screening of (E)-3-(2-benzylidenehydrazinyl)-5,6-diphenyl-1,2,4-triazine analogs as novel dual inhibitors of α-amylase and α-glucosidase

Bioorg Chem. 2020 Aug:101:103979. doi: 10.1016/j.bioorg.2020.103979. Epub 2020 Jun 1.

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 Chemistry Department, King Fahd University of Petroleum & Minerals, Dhahran-31261, Saudi Arabia.
⁴ Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Qassim University, Buraidah 52571, Saudi Arabia.
⁵ Department of Biochemistry, Shankar Campus, Abdul Wali Khan University, Mardan, Khyber Pukhtoonkhwa, Pakistan.
⁶ Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
⁷ Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Buraidah 51452, Saudi Arabia.
⁸ Department of Clinical Pharmacy, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, P.O. Box 31441, Dammam, Saudi Arabia.
⁹ PCSIR Laboratories Complex, Karachi, Shahrah-e-Dr. Salimuzzaman Siddiqui, Karachi-75280, Pakistan.

PMID: 32544738
DOI: 10.1016/j.bioorg.2020.103979

Abstract

(E)-3-(2-Benzylidenehydrazinyl)-5,6-diphenyl-1,2,4-triazines analogs 1-27 were synthesized by multi-step reaction scheme and subjected to in vitro inhibitory screening against α-amylase and α-glucosidase enzymes. Out of these twenty-seven synthetic analogs, ten compounds 14-17, 19, and 21-25 are structurally new. All compounds exhibited good to moderate inhibitory potential in terms of IC₅₀ values ranging (IC₅₀ = 13.02 ± 0.04-46.90 ± 0.05 µM) and (IC₅₀ = 13.09 ± 0.08-46.44 ± 0.24 µM) in comparison to standard acarbose (IC₅₀ = 12.94 ± 0.27 µM and 10.95 ± 0.08 µM), for α-amylase and α-glucosidase, respectively. Structure-activity relationship indicated that analogs with halogen substitution(s) were found more active as compared to compounds bearing other substituents. Kinetic studies on most active α-amylase and α-glucosidase inhibitors 5, 7, 9, 15, 24, and 27, suggested non-competitive and competitive types of inhibition mechanism for α-amylase and α-glucosidase, respectively. Molecular docking studies predicted the good protein-ligand interaction (PLI) profile with key interactions such as arene-arene, H-<, <-<, and <-H etc., against the corresponding targets.

Keywords: 1, 2, 4-Triazine, in vitro screening; Acarbose; Kinetics; Molecular modeling; Structure-activity relationship; α-amylase inhibition; α-glucosidase inhibition.

Publication types

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

MeSH terms

Acarbose / therapeutic use*
Diabetes Mellitus, Type 2 / diet therapy*
Humans
Molecular Docking Simulation / methods*
Molecular Structure
Structure-Activity Relationship
Triazines / chemistry*
alpha-Amylases / antagonists & inhibitors*
alpha-Glucosidases / chemistry*

Substances

Triazines
1,2,4-triazine
alpha-Amylases
alpha-Glucosidases
Acarbose