Design, synthesis, and biological evaluation of pyrimidine linked fused thiazole-isoxazole conjugates as dual cholinesterase inhibitors for Alzheimer’s disease

AI Summary

Pyrimidine-clubbed thiazolo[4,5-c]isoxazole scaffold yields potent dual AChE/BuChE inhibitors; lead compound IC50s 6.19 μM and 8.64 μM, outperforming donepezil.
Structure activity relationship analysis identified aryl substituents p-CF3, p-F, o,p-Cl, p-NO2 and p-OH as principal potency modulators.
Molecular docking shows dual engagement of catalytic and peripheral anionic sites via hydrogen bonding and π-π stacking; in silico ADMET supports drug likeness and reactivity.

TL;DR (AI Generated)

Here, we report a series of pyrimidine clubbed thiazolo[4,5-c]isoxazole framework that functions as potent dual cholinesterase inhibitors with low-micromolar activity against both AChE and BuChE.

Lead compound-1 demonstrated IC50 values of 6.19 ± 0.60 μM (AChE) and 8.64 ± 0.91 μM (BuChE) showing promising performance over the reference donepezil (AChE IC50 = 19.38 ± 0.98 μM, BuChE IC50 = 27.54 ± 1.34 μM).

Moreover, molecular docking against human AChE and BuChE crystal structures revealed dual engagement of the catalytic anionic site and peripheral anionic site through hydrogen-bonding and π-π stacking interactions.

Basic summary

Z Naturforsch C J Biosci. 2026 Oct 12. doi: 10.1515/znc-2026-0143. Online ahead of print.

ABSTRACT

Alzheimer’s disease (AD) affects over 55 million individuals worldwide, yet approved pharmacotherapies remain limited to symptomatic relief. Dual inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) offers a validated approach to restoring cholinergic tone. However, structurally differentiated inhibitors with favorable selectivity profiles are critically needed. Here, we report a series of pyrimidine clubbed thiazolo[4,5-c]isoxazole framework that functions as potent dual cholinesterase inhibitors with low-micromolar activity against both AChE and BuChE. Lead compound-1 demonstrated IC₅₀ values of 6.19 ± 0.60 μM (AChE) and 8.64 ± 0.91 μM (BuChE) showing promising performance over the reference donepezil (AChE IC₅₀ = 19.38 ± 0.98 μM, BuChE IC₅₀ = 27.54 ± 1.34 μM). Furthermore, structure-activity relationship analysis identified electron-withdrawing (p-CF₃, p-F, o,p-Cl, p-NO₂) and electron-donating (-OH) aryl substituents as principal modulators of inhibitory potency. Moreover, molecular docking against human AChE and BuChE crystal structures revealed dual engagement of the catalytic anionic site and peripheral anionic site through hydrogen-bonding and π-π stacking interactions. In silico ADMET profiling confirmed electronic reactivity and drug-likeness of lead compounds. These findings establish pyrimidine-clubbed thiazolo[4,5-c]isoxazole as a mechanistically grounded scaffold with translational potential for next-generation anti-Alzheimer therapeutics.

PMID:42855983 | DOI:10.1515/znc-2026-0143

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