Design, Synthesis and Molecular Docking Studies of Some Novel Hydrazone Derivatives Based on Trimetazidine as Selective and Potent AChE Inhibitors
DRUG DEVELOPMENT RESEARCH, vol.87, no.7, 2026 (SCI-Expanded, Scopus)
- Publication Type: Article / Article
- Volume: 87 Issue: 7
- Publication Date: 2026
- Doi Number: 10.1002/ddr.70382
- Journal Name: DRUG DEVELOPMENT RESEARCH
- Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, Chemical Abstracts Core, EMBASE, MEDLINE, Academic Search Ultimate (EBSCO), Natural Science Collection (ProQuest), Biological Science Database (ProQuest), Biomedical Reference Collection: Corporate Edition (EBSCO), Health Research Premium Collection (ProQuest)
- Anadolu University Affiliated: Yes
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disease, and cholinergic dysfunction is considered one of the fundamental pathological factors of this disease. Guided by the clinically used acetylcholinesterase (AChE) inhibitor donepezil, we explored trimetazidine dihydrochloride as an accessible starting scaffold to generate donepezil-like features and to develop new anti-AD candidates. Accordingly, 20 novel hydrazone derivatives were designed and synthesized based on trimetazidine dihydrochloride, and their structures were confirmed by spectroscopic methods. The compounds were evaluated for in vitro inhibition of AChE and butyrylcholinesterase (BChE) using donepezil and tacrine as reference inhibitors, respectively. Several derivatives displayed pronounced AChE inhibition, whereas most compounds showed weak or negligible activity toward BChE, indicating a generally favorable AChE-selective profile. Among the series, compounds 3p, 3q and 3r exhibited selective inhibitory activity against AChE comparable to donepezil, with IC50 values of 0.030 +/- 0.001 mu M, 0.085 +/- 0.003 mu M and 0.034 +/- 0.001 mu M, respectively. To rationalize the observed activity trends, molecular docking studies were performed, suggesting that the most active ligands adopt donepezil-like binding modes spanning the catalytic and peripheral anionic sites and are further stabilized by pi-pi/pi-cation contacts and hydrogen-bonding interactions within the active gorge. Overall, these findings identify trimetazidine-derived hydrazide-hydrazones as a promising chemotype for the development of selective AChE inhibitors and provide a basis for further optimization and advanced biological validation.