Identification of Indazole-Based Thiadiazole-Bearing Thiazolidinone Hybrid Derivatives: Theoretical and Computational Approaches to Develop Promising Anti-Alzheimer's Candidates

A hybrid library of compounds based on indazole-based thiadiazole containing thiazolidinone moieties ( - ) was synthesized. The synthesized compounds were screened in vitro for their inhibition profile against targetedacetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities. All the derivatives demonstrated a varied range of inhibitory activities having IC values ranging from 0.86 ± 0.33 μM to 26.73 ± 0.84 μM (AChE) and 0.89 ± 0.12 μM to 27.08 ± 0.19 μM (BuChE), respectively. The results obtained were compared with standard Donepezil drugs (IC = 1.26 ± 0.18 μM for AChE) and (1.35 ± 0.37 μM for BuChE), respectively. Specifically, the derivatives - , , , and were found to be significantly active, with IC values of 0.86 ± 0.30, 0.92 ± 0.10, and 1.10 ± 0.37 μM (against AChE) and 0.89 ± 0.12, 0.98 ± 0.48 and 1.19 ± 0.42 μM (against BuChE), respectively.The structure-activity relationship (SAR) studies revealed that derivatives bearing -CF , -OH, and -F substitutions on the phenyl ring attached to the thiadiazole skeleton, as well as -Cl, -NO , and -chloro substitutions on the phenyl ring, having a significant effect on inhibitory potential. The synthesized scaffolds have been further characterized by using H-NMR, C-NMR, and (HR-MS) to confirm the precise structures of the synthesized compounds. Additionally, the molecular docking approach was carried out for most active compounds to explore the binding interactions established by most active compounds, with the active sites of targeted enzymes and obtained results supporting the experimental data.