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Design, Synthesis, in Vitro, and in Silico Assessment of New Thiosemicarbazone-Indole-1,2,3-Triazole-Acetamide Derivatives As Potent Dual Inhibitors of Acetylcholinesterase and Carbonic Anhydrase Publisher



Dastyafteh N ; Taherkhani AM ; Halimi M ; Naz F ; Ghafouri SN ; Mohammadikhanaposhtani M ; Aktas A ; Sadeghian N ; Dadgar A ; Biglar M ; Larijani B ; Khan KM ; Taslimi P ; Mahdavi M
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Source: Journal of Molecular Structure Published:2026


Abstract

In this study, we report the synthesis, characterization, and enzyme inhibition effects of new thiosemicarbazone-indole-1,2,3-triazole-acetamide derivatives. All compounds were characterized by using NMR and FTIR spectroscopic and elemental analysis techniques. All new thiosemicarbazone-indole-1,2,3-triazole-acetamide derivatives (12a-q) were examined as potential inhibitors against acetylcholinesterase (AChE) and two key human carbonic anhydrases (hCA I and II), which are important in the treatment of Alzheimer’s disease. Enzymatic evaluations showed that all new compounds were more potent than the standard inhibitor tacrine against AChE, and most were more potent than the standard drug acetazolamide against carbonic anhydrases. Specifically, the best compound against AChE (12f) was 93.2-fold more potent than tacrine, while the best compounds against hCA I (12l) and hCA II (12m) were 2.4-fold and 2.3-fold more potent than acetazolamide, respectively. By molecular modeling study, compounds 12f, 12l, and 12m were placed into the active sites of AChE, hCA I, and hCAII, and the docking data agreed with the in vitro findings. Furthermore, molecular dynamics simulations demonstrated that compound 12f formed a stable complex with AChE. © 2026 Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.
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