Hussain_2026_J.Comput.Aided.Mol.Des_40_

The complex pathology of Alzheimer's disease (AD), together with the limited effectiveness of current treatments, has sparked the search for multifunctional agents capable of targeting key pathological mechanisms simultaneously. In this study, a novel series of cyclopropyl-appended thiohydantoin derivatives 4a-d and their corresponding S-substituted analogues 6a-d were rationally designed and synthesized as multi-target agents. Following complete spectroscopic characterization ((1)H NMR/(13)C NMR and HRMS), the entire library of synthesized compounds was evaluated for multi-target potential, including cholinesterase inhibition, cyclooxygenase selectivity, and DPPH radical scavenging efficacy. Biological evaluation revealed that the S-alkylated derivatives 6a-d exhibited superior activities as compared to their parent analogues 4a-d. Multi-target screening identified compounds 6a and 6c as multifunctional leads exhibiting balanced cholinesterase inhibitory, COX-2 inhibitory, and antioxidant activities. Compound 6a demonstrated potent COX-2 inhibition with an IC(50) value of 0.32 +/- 0.05 microM and a high selectivity index (SI = 36.81), outperforming the reference drug celecoxib (IC(50 )= 0.41 +/- 0.05 microM). In contrast, compound 6c displayed the highest radical scavenging potential in the DPPH assay (IC(50) = 24.85 +/- 0.96 microM), comparable to that of gallic acid. Together with their dual cholinesterase inhibitory activities, compounds 6a and 6c represent promising multifunctional in vitro lead candidates for further development against neurodegenerative disorders associated with neuroinflammation and oxidative stress. Comprehensive structure activity relationship (SAR) analysis highlighted that the S-alkylation and aromatic substitution had beneficial effects on biological activity. Furthermore, density functional theory (DFT) calculations demonstrated that the lead compounds possessed favorable electronic properties, while molecular docking and molecular dynamics simulations revealed favorable binding interactions with the active sites of AChE, BuChE, and COX-2 and stable ligand-protein complex formation. Additionally, in silico ADMET profiling confirmed acceptable general oral drug-likeness and low toxicity risks for the most active compounds; however, central nervous system (CNS)-specific analysis indicated restricted predicted blood-brain barrier (BBB) permeability, highlighting a key area for future structural optimization. Collectively, this study identifies cyclopropyl-appended thiohydantoin derivatives as potential multifunctional scaffolds for the development of novel anti-Alzheimer agents targeting cholinergic dysfunction, oxidative stress, and neuroinflammation.