Design, synthesis, biological activities, and evaluation of molecular docking-dynamics studies of new thiosemicarbazones that may be effective against Alzheimer's disease

Conger N., OSMANİYE D., SAĞLIK B. N., LEVENT S., ÖZKAY Y., KAPLANCIKLI Z. A.

JOURNAL OF MOLECULAR RECOGNITION, cilt.36, sa.12, 2023 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 36 Sayı: 12
  • Basım Tarihi: 2023
  • Doi Numarası: 10.1002/jmr.3059
  • Dergi Adı: JOURNAL OF MOLECULAR RECOGNITION
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, Aerospace Database, BIOSIS, Biotechnology Research Abstracts, Chemical Abstracts Core, Communication Abstracts, MEDLINE, Metadex, Civil Engineering Abstracts
  • Anahtar Kelimeler: AChE, molecular docking, molecular dynamics, piperazine, thiosemicarbazone
  • Anadolu Üniversitesi Adresli: Evet

Özet

Donepezil is one of the most used drugs in the treatment of Alzheimer's disease. Its activity as an AChE inhibitor makes new studies with these enzyme inhibitors attractive. For this purpose, in this study, 12 compounds including thiosemicarbazone pharmacophore, have been synthesized for the treatment of the Alzheimer's disease. 3,4-Dimethoxybenzene or 1,3-benzodioxolone rings were used for the PAS region. The substituted piperazine benzene structure is preferred for the CAS region. At the same time, the thiosemicarbazone pharmacophore structure with known ChE enzyme inhibition potential was used as a bridge connecting the CAS and PAS regions. Structure determination of compounds 3a-3l were revealed using C-13-NMR, H-1-NMR, and HRMS spectroscopic methods. The inhibition profile of obtained compounds (3a-3l) against ChE was evaluated using in vitro modified Ellman method. Compounds 3a, 3b, 3f, 3g and 3i exhibited inhibitory activity against the AChE enzyme. Compound 3a showed the highest inhibitory potential with an IC50 = 0.030 +/- 0.001 mu M. As a result of molecular docking studies, compound 3a displayed important interactions compared to other active derivatives. Molecular dynamics studies are important to see the stability of the complex formed by ligand and protein. RMSD, RMSF ang Rg parameters were calculated via dynamic studies. In conclusion, compound 3a may be a potential AChE enzyme inhibitor with its strong inhibitory potential and behavior in silico.