Journal Article Epublish 6 citations
PubMed: 40430294 DOI: 10.3390/molecules30102121
Synthesis, Biological Evaluation, and Molecular Docking Studies of Novel Coumarin-Triazole-Isatin Hybrids as Selective Butyrylcholinesterase Inhibitors.
Molecules 30(10)
Authors: Aleksandar Dimkovski, Vladimir Dobričić, Milena R Simić, Maja Jurhar Pavlova, Evgenija Mihajloska, Zoran Sterjev, Ana Poceva Panovska
Affiliations
- Institute for Pharmaceutical Chemistry, Faculty of Pharmacy, Ss Cyril and Methodius University in Skopje, 1000 Skopje, North Macedonia.
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, 11221 Belgrade, Serbia.
- Department of Organic Chemistry, Faculty of Pharmacy, University of Belgrade, 11221 Belgrade, Serbia.
- Institute for Microbiology and Parasitology, Faculty of Medicine, Ss Cyril and Methodius University in Skopje, 1000 Skopje, North Macedonia.
- Institute for Applied Chemistry and Pharmaceutical Analysis, Faculty of Pharmacy, Ss Cyril and Methodius University in Skopje, 1000 Skopje, North Macedonia.
Abstract
A series of 21 novel coumarin-triazole-isatin hybrids was synthesized and evaluated for their potential as multitarget agents in Alzheimer's disease (AD). The compounds featured variations in alkyl linker length that connects coumarin and triazole and substitution at the 5-position of the isatin ring. Several derivatives showed potent butyrylcholinesterase (BChE) inhibition with selectivity over acetylcholinesterase (AChE). The lead compound, 6c1, exhibited strong BChE inhibition (IC 50 = 1.74 μM), surpassing donepezil. Enzyme kinetics revealed a mixed-type mechanism, while molecular docking studies confirmed dual binding at catalytic and peripheral sites. Structure-activity relationship (SAR) analysis highlighted the influence of linker flexibility and steric/electronic effects of substituents. The observed BChE selectivity, combined with favorable in vitro profiles, identifies these hybrids as promising leads for AD drug development.
MeSH
Isatin, Butyrylcholinesterase, Triazoles, Cholinesterases