Synthesis of tetrazole-linked phenothiazines as cholinesterase inhibitors: In vitro approach combined with molecular docking, molecular dynamics, and anti-tuberculosis studies

Akdoğan N., Adem Ş., Eyüpoğlu V., DİŞLİ A., Mayda P. Y., DOYDUK D., ...Daha Fazla

Journal of Molecular Structure, cilt.1348, 2025 (SCI-Expanded) identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 1348
  • Basım Tarihi: 2025
  • Doi Numarası: 10.1016/j.molstruc.2025.143569
  • Dergi Adı: Journal of Molecular Structure
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, Chemical Abstracts Core, Chimica, Compendex, INSPEC
  • Anahtar Kelimeler: Acetylcholinesterase, Butyrylcholinesterase, Molecular dynamics, Mycobacterium tuberculosis, Phenothiazine, Tetrazole
  • Gazi Üniversitesi Adresli: Evet

Özet

Heteroatom-containing compounds are key in drug development due to their ability to increase hydrogen bonding, aiding biological receptor binding. Tetrazole and phenothiazine are vital pharmacological frameworks for genetic manipulation. In this study, novel bioactive phenothiazine derivatives containing a tetrazole ring were synthesized, and their molecular structures were analyzed using spectroscopic techniques (FT-IR, NMR, HR-MS, X-Ray for F5f). The compounds were tested against Mycobacterium tuberculosis and cholinesterase enzymes and showed minimum inhibitory concentration (MIC) values of 500-125 µg/mL against the M. tuberculosis strain. Some compounds showed superior inhibitory effects on cholinesterase enzymes compared to standard molecules. F5c, F4e, and F5g inhibited the AChE enzyme with IC50 values of 0.88-3.12 μM, while F5b, F3e, and F3h targeted the BChE enzyme with IC50 values of 16.50-18.24 μM. F5c and F4e also competitively inhibited AChE with Ki values of 0.27±0.03 and 0.96±0.12 μM, respectively. Docking studies confirmed the efficient interaction with enzyme active sites. Molecular dynamics simulations of F5c with acetylcholinesterase (4EY7) showed significant binding affinity (-72.73 Kcal/mol). These results highlight the potential of F5c to modulate acetylcholinesterase activity relevant for the treatment of neurological disorders. Furthermore, DFT analysis provided quantum mechanical insights into molecular docking and dynamics.