Targeting enzyme inhibition with triazole-functionalized 5-arylideneura-cils: Synthesis, structural and computational insights

Uracil-appended organic ligands are interesting molecules in terms of enzyme inhibition studies as a result of their multifunctional structures. Herein, a series of novel 1,2,3-triazole substituted 5-arylideneuracils were obtained via click chemistry in a two-step procedure with moderate to good yields (28-67% yields). All of the compounds were characterized using Fourier transform infrared spectroscopy (FT-IR), proton and carbon nuclear magnetic resonance spectroscopy (1H and 13C NMR) and high resolution mass spectrometry (HR-MS). The inhibition abilities of novel 5-arylideneuracils (2a-2j) were evaluated against acetylcholinesterase (AChE) and human carbonic anhydrase I and II (hCA I and II) isoenzymes which are mainly associated with some global disorders such as Alzheimer's disease (AD), diabetes, epilepsy, and glaucoma. The compounds exhibited inhibition profiles with Ki values ranging from 4.21+1.51 nM to 52.79+10.58 nM for AChE, 130.80+34.34-410.40 +32.44 nM for hCA I and 64.25 + 7.62-614.40+98.45 for hCA II. Tacrine was used as a reference inhibitor for AChE and exhibited a Ki value of 2.59+0.91 nM against the AChE enzyme. On the other hand, Acetazolamide was used as a standard inhibitor towards hCA I and hCA II isoforms with Ki values of 81.0 + 14.0 nM and 258.0 + 92.0 nM, respectively. The inhibition results related to key metabolic and neurological enzymes suggest that novel 5-arylideneuracils may serve as promising candidates for the development of new drugs targeting global diseases such as Alzheimer's disease (AD), glaucoma, and epilepsy. To elucidate the binding interactions of these compounds with AChE, hCA I, and hCA II, molecular docking simulations were performed. Compound 2i has shown superior activity in vitro and in both docking and molecular dynamics simulations, indicating its potential as a promising alternative to tacrine for AChE inhibition.

Dergi

JOURNAL OF MOLECULAR STRUCTURE

Yıl

2026

Cilt

1364

ISSN

0022-2860

eISSN

1872-8014

DOI

10.1016/j.molstruc.2026.145905

WoS UID

WOS:001717200700001