3(2H)-pyridazinone derivatives: Synthesis, in-silico studies, structure-activity relationship and in-vitro evaluation for acetylcholinesterase enzyme inhibition

Col O. F., BOZBEY İ., TÜRKMENOĞLU B., Uysal M.

JOURNAL OF MOLECULAR STRUCTURE, cilt.1261, 2022 (SCI-Expanded) identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 1261
  • Basım Tarihi: 2022
  • Doi Numarası: 10.1016/j.molstruc.2022.132970
  • Dergi Adı: JOURNAL OF MOLECULAR STRUCTURE
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, Chemical Abstracts Core, INSPEC
  • Anahtar Kelimeler: 3(2H)-pyridazinone, 4D-QSAR, AChE inhibitor, Alzheimer?s disease, Molecular docking, ALZHEIMERS-DISEASE, CHOLINERGIC SYSTEM, MOLECULAR DOCKING, 4D-QSAR, SERIES, BUTYRYLCHOLINESTERASE, AGGREGATION, PREVALENCE, CHALLENGES, HYPOTHESIS
  • Gazi Üniversitesi Adresli: Evet

Özet

New ten compounds bearing pyridazinone ring (5a -j) were designed and synthesized as acetyl-cholinesterase inhibitors. The new derivatives were acquired via the reaction of propionohydrazides with substituted/nonsubstituted sulphonylchlorides. The structures of the synthesized compounds were explained using FT-IR, H-1-NMR, C-13-NMR, elemental analysis and HRMS spectra. The inhibition profiles of the synthesized compounds on AChE were researched by comparing their IC(50 )and K-I values. According to the activity studies, all the compounds showed significant inhibitory activity against AChE relative to the reference compound Tacrine. The compound 5g showed the best acetylcholinesterase inhibitory effect with a KI value of 11.61 +/- 0.77 nM. For all compounds, the parameters of the interaction points on the receptor side were determined on the ligand basis with the 4D-QSAR model. The synthesized pyridazinone derivatives, 5(a-j) , were screened for their acetylcholinesterase inhibitory potential, and the results determined that among the series, compounds 5g, 5f and 5j showed the best inhibition, respectively. For anti-Alzheimer activities, 5g, 5f and 5j compounds were performed in silico studies to understand the binding site, binding energy properties in molecular docking. (C) 2022 Elsevier B.V. All rights reserved.