Pyridazine Derivatives as New Antidiabetic Agents: Synthesis, In‐Vitro α‐Amylase Inhibitory Activity, Molecular Docking and Molecular Dynamics Simulations Studies

Author:

Boukharsa Youness12,Alhaji Isa Mustafa34,Sayah Karima5,Alsalme Ali6,Oulmidi Afaf7,Shehzadi Somia8,El Abbes Faouzi My5,Karrouchi Khalid9ORCID,Ansar M'hammed1

Affiliation:

1. Laboratory of Therapeutic Chemistry Faculty of Medicine and Pharmacy Mohammed V University in Rabat Rabat Morocco

2. Higher Institue of Nursing Professions and Technical Health (ISPITS) in Casablanca Casablanca Morocco

3. Department of Biochemistry, Faculty of Science University of Johannesburg, <Johannesburg South Africa

4. Department of Microbiology, Faculty of Life Science University of Maiduguri Maiduguri Nigeria

5. Laboratory of Pharmacology and Toxicology Faculty of Medicine and Pharmacy University Mohammed V in Rabat Rabat Morocco

6. Department of Chemistry, College of Science King Saud University Riyadh 11451 Saudi Arabia

7. Institute of Condensed Matter and Nanosciences Molecular Chemistry, Materials and Catalysis (IMCN/MOST) Université Catholique de Louvain 1348 Louvain-la-Neuve Belgium

8. Institute of Medical Laboratory Technology University of Lahore Lahore Pakistan

9. Laboratory of Analytical Chemistry and Bromatology Faculty of Medicine and Pharmacy Mohammed V University in Rabat Rabat Morocco

Abstract

AbstractThis study involved the synthesis, characterization, and assessment of fourteen pyridazine analogs (designated as 114) to investigate their efficacy in inhibiting the α‐amylase enzyme for potential diabetes treatment using an in vitro approach. Additionally, in silico molecular docking and molecular dynamic (MD) simulations were conducted to assess the inhibitory properties of these analogs. Physicochemical and pharmacokinetic properties of the fourteen pyridazine analogs were predicted using the DataWarrior tool. Results indicated that all tested compounds demonstrated significant α‐amylase inhibitory activity, with IC50 values ranging from 81.28±0.00 to 1623.54±2.67 μM compared to the standard drug acarbose (IC50=220.42±36.40 μM). Notably, compounds 8 and 12 exhibited the most potent α‐amylase inhibitory activity, with IC50 values of 81.28±0.00 μM and 200.60±34.65 μM, respectively. Molecular docking analysis revealed binding energies ranging from −7.53 to −5.77 kcal/mol and inhibition constants ranging from 3.00 to 58.96 μM, with compounds 9, 7, 8, 5, and 3 demonstrating the best binding energies. Subsequent MD simulation analyses indicated that all five compound formed stable complexes after 100 ns MD simulation. Consequently, these compounds hold promise as potential α‐amylase inhibitors pending successful clinical validation.

Funder

King Saud University

Publisher

Wiley

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