Almatary_2025_Bioorg.Chem_157_108295

Novel 2,4-thiazolidinedione-benzothiazole-triazole hybrids (7a-7l) were designed and synthesized as therapeutic agents with pleotropic activity for Alzheimer's disease (AD). These compounds were evaluated for their acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activities. Compound 7k, exhibited exceptional AChE inhibition (IC50 = 0.083 microM), while compound 7d, showed potent activity (IC50 = 0.119 microM). Kinetic studies revealed that 7k was able to exert its action through mixed types of inhibition. Also, the anti-inflammatory potential of these lead compounds was assessed in LPS-stimulated RAW 264.7 macrophages. Both compounds demonstrated significant dose-dependent inhibition of key inflammatory mediators, including NO, TNF-alpha, IL-6, and IL-1beta at non-cytotoxic concentrations (>=10 microM). Notably, compound 7k exhibited superior anti-inflammatory activity, achieving 92 % NO inhibition, 65 % TNF-alpha reduction, and 61.1 % IL-1beta suppression at 10 microM. Moreover, compound 7k exerted neuroprotective activity against H(2)O(2) induced neurotoxicity in SH-Sy5y cell line leading to reduction in LDH, ROS levels and improving cell survival. Finally, compound 7k was able to prevent Abeta aggregation at IC(50) = 5 microM. Molecular docking studies provided structural insights into the possible binding interactions of compounds 7d and 7k within the AChE active site. The stability and binding energies of compounds 7d and 7k complexed with AChE were assessed over 100 ns molecular dynamics simulations and compared with Donepezil. The MM/GBSA binding energy calculations indicated that compound 7k exhibited a higher affinity for AChE in comparison with compound 7d and Donepezil, with deltaG(binding) values of -46.1, -42.6, and - 24.0 kcal/mol, respectively. These findings suggest that these novel hybrid molecules represent promising multi-target therapeutic candidates for AD treatment, effectively addressing both cholinergic dysfunction and neuroinflammation.