Design, synthesis, and molecular modeling of new 3(2H)-pyridazinone derivatives as acetylcholinesterase/butyrylcholinesterase inhibitors

ÖZDEMİR Z., Yilmaz H., SARI S., KARAKURT A., ŞENOL DENİZ F. S., UYSAL M.

MEDICINAL CHEMISTRY RESEARCH, cilt.26, sa.10, ss.2293-2308, 2017 (SCI-Expanded) identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 26 Sayı: 10
  • Basım Tarihi: 2017
  • Doi Numarası: 10.1007/s00044-017-1930-x
  • Dergi Adı: MEDICINAL CHEMISTRY RESEARCH
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Sayfa Sayıları: ss.2293-2308
  • Anahtar Kelimeler: AChE inhibitory, BChE inhibitory, 3(2H)-Pyridazinone, Benzalhydrazone, Molecular docking, BIOLOGICAL EVALUATION, HUMAN BUTYRYLCHOLINESTERASE, HUMAN ACETYLCHOLINESTERASE, AMYLOID AGGREGATION, CRYSTAL-STRUCTURE, ACCURATE DOCKING, DUAL INHIBITORS, ALZHEIMERS, POTENT, BETA
  • Gazi Üniversitesi Adresli: Evet

Özet

Inhibition of cholinesterases is an effective method to curb Alzheimer's disease, a progressive and fatal neurological disorder. A series of 6-substituted-3(2H)-pyridazinone-2-acetyl-2-(p-substituted benzalhidrazone) derivatives were designed, synthesized, and their inhibitory effects on acetylcholinesterase and butyrylcholinesterase were evaluated in pursuit of potent dual inhibitors. We obtained our compounds by the reaction of various substituted/nonsubstituted benzaldehydes with 6-[4-(3,4-dichlorophenyl)piperazine-1-yl]-3(2H)-pyridazinone-2-yl acetohydrazide and determined their anticholinesterase activities according to the Ellman's method. 5f and 5i showed 75.52 and 71.72% acetylcholinesterase inhibition at 100 A mu g/ml, respectively. 5h and 5f, on the other hand, were the best butyrylcholinesterase inhibitors with 67.16 and 62.03% inhibition at the same concentration, respectively. 5f emerged as a potent dual cholinesterase inhibitor. Through molecular docking studies we predicted the inhibition mechanism of 5f for both enzymes in comparison with our previous derivatives, which differ in inhibition potency, and tried to get insights into the factors that affect receptor affinity in molecular level.