Khan_2023_Pharmaceuticals.(Basel)_16_

A hybrid library of compounds based on indazole-based thiadiazole containing thiazolidinone moieties (1-17) 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(50) values ranging from 0.86 +/- 0.33 microM to 26.73 +/- 0.84 microM (AChE) and 0.89 +/- 0.12 microM to 27.08 +/- 0.19 microM (BuChE), respectively. The results obtained were compared with standard Donepezil drugs (IC(50) = 1.26 +/- 0.18 microM for AChE) and (1.35 +/- 0.37 microM for BuChE), respectively. Specifically, the derivatives 1-17, 1, 9, and 14 were found to be significantly active, with IC(50) values of 0.86 +/- 0.30, 0.92 +/- 0.10, and 1.10 +/- 0.37 microM (against AChE) and 0.89 +/- 0.12, 0.98 +/- 0.48 and 1.19 +/- 0.42 microM (against BuChE), respectively.The structure-activity relationship (SAR) studies revealed that derivatives bearing para-CF(3), ortho-OH, and para-F substitutions on the phenyl ring attached to the thiadiazole skeleton, as well as meta-Cl, -NO(2), and para-chloro substitutions on the phenyl ring, having a significant effect on inhibitory potential. The synthesized scaffolds have been further characterized by using (1)H-NMR, (13)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.