Isovanillin-derived bis-hydrazones as dual cholinesterase and carbonic anhydrase inhibitors: synthesis, enzymatic profiling, and computational insights from molecular docking and dynamics

TÜRKEŞ C., Yapar G., Duran H. E., Lolak N., Akocak S.

Future Medicinal Chemistry, vol.18, no.3, pp.237-253, 2026 (SCI-Expanded, Scopus) identifier identifier

  • Publication Type: Article / Article
  • Volume: 18 Issue: 3
  • Publication Date: 2026
  • Doi Number: 10.1080/17568919.2026.2617608
  • Journal Name: Future Medicinal Chemistry
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Chemical Abstracts Core, EMBASE, MEDLINE
  • Page Numbers: pp.237-253
  • Keywords: ADMET profiling, bis-hydrazone derivatives, carbonic anhydrase inhibition, cholinesterase inhibition, Isovanillin, molecular docking, molecular dynamics
  • Erzincan Binali Yildirim University Affiliated: Yes

Abstract

Aims: To develop isovanillin-based bis-hydrazones as multitarget inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and human carbonic anhydrase I/II (hCA I/II). Materials & methods: Twelve bis-hydrazones (4a–4l) were synthesized in two steps and evaluated by spectrophotometric enzyme assays, Lineweaver–Burk kinetics, molecular docking, MM-GBSA, molecular dynamics simulations, and in silico ADME/Tox profiling. Results: All compounds showed nanomolar inhibition. Compound 4d was the most potent AChE/BChE inhibitor (KI = 10.46 and 3.56 nM), while 4a and 4j led the hCA I/II panel (KI = 3.46 and 16.12 nM). Docking, MM-GBSA, and molecular dynamics supported dual-site cholinesterase engagement and non-zinc, peripherally anchored hCA inhibition. Conclusions: Isovanillin-based bis-hydrazones, particularly 4d, 4a, and 4j, represent promising multitarget leads for cholinergic and hCA-linked disorders.