Pyridazinones containing the (4-methoxyphenyl)piperazine moiety as AChE/BChE inhibitors: design, synthesis, in silico and biological evaluation

Bozbey İ., Taşkor Önel G., Türkmenoğlu B., Gürsoy Ş., Dilek E.

MEDICINAL CHEMISTRY RESEARCH, vol.31, no.11, pp.2021-2031, 2022 (SCI-Expanded) identifier identifier

  • Publication Type: Article / Article
  • Volume: 31 Issue: 11
  • Publication Date: 2022
  • Doi Number: 10.1007/s00044-022-02968-x
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, CAB Abstracts, Chemical Abstracts Core, Chimica, EMBASE, Veterinary Science Database
  • Page Numbers: pp.2021-2031
  • Keywords: 3(2H)-pyridazinone, 1,2,4-triazole, AChE/BChE inhibitory activity, Alzheimer's disease, Molecular docking
  • Erzincan Binali Yildirim University Affiliated: Yes


Alzheimer’s disease is a progressive and fatal neurodegenerative disease affecting the elderly population accompanied by a decrease in cholinergic transmission, impairing cognitive functions. Acetylcholine deficiency is important in the development of disease symptoms. Inhibition of acetylcholinesterase, an important enzyme in acetylcholine hydrolysis, is one of the important drug targets to increase acetylcholine levels. In this study, we aimed to develop acetylcholinesterase inhibitor compounds. For this, we synthesized compounds 6(a–e) bearing 3(2H)-pyridazinone and 1,2,4-triazole ring structures. We determined the IC50Ki and inhibition types of N-substituted-(p-methoxyphenyl)pyridazin-3(2H)-one derivatives that we synthesized and elucidated their structures. The compound with the best AChE activity was compound 6b (Ki = 3.73 ± 0.9 nM) with the p-methylphenyl group it carried and showed competitive inhibition. Kinetic study was also performed for the compounds with the highest BChE 6a (Ki = 0.95 ± 0.16 nM) inhibitory activities. Molecular docking studies have shown that the p-methylphenyl group is indeed active in the hinge region of the AChE crystal structure as a result of experimental activity. In addition, the best free binding energy (ΔGBind), docking score and Glide score values were determined by examining the interactions with AChE crystal structure for compound 6b and with BChE crystal structure for 6a in silico approaches.