4-methylbenzyl 5-arylthiophene-2-carboxylates as Multitarget Directed Ligands Scaffolds (MTDLs): Synthesis, in-silico docking studies, and evaluation of dual selective enzymatic inhibition (AChE & MAO-B).

Authors

Aqsa Kanwal, Nasir Rasool

Published in

Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents. Volume 35. Issue 2. Pages 425-436. Epub Jan 12, 2026.

Abstract

Single-target ligands have insufficient effectiveness in treating Alzheimer's disease (AD), leading to the development of new pharmacological strategies, particularly multi-target-directed ligands (MTDLs) that tackle the multifactorial nature of the impairment. Among these, dual inhibition of acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B) represents a promising approach for enhancing therapeutic outcomes. Here, analogs of 4-methylbenzyl 5-arylthiophene-2-carboxylates (5a-5h) were identified as dual inhibitors of AChE and MAO-B. In vitro evaluations demonstrated that 5a-5d exhibited the most promising inhibition potential towards targeted enzymes (AChE and MAO-B), having IC₅₀ values 0.72 ± 0.01 µM to 1.69 ± 0.04 µM for AChE and 0.19 ± 0.03 µM to 2.69 ± 0.10 µM for MAO-B. Docking analysis is consistent with the in vitro studies, critically unveiling bindings, commonly hydrogen interactions, π-Sulphur, π-π interaction, π-alkyl, and alkyl-alkyl ligand and enzyme binding interactions. These results underscore the promise of these dual inhibitors in tackling the complex pathology of AD.

PMID:
42446696
Bibliographic data and abstract were imported from PubMed on 14 Jul 2026.

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