Khan_2024_Biochem.Biophys.Res.Commun_726_150201

In the current research study, we aim to design and synthesize highly potent hybrid analogs of benzimidazole derived thiadiazole based Schiff base derivatives which can combat the cholinesterase enzymes (acetylcholinesterase and butyrylcholinesterase) accountable for developing Alzheimer's disease. In this context, we have synthesized 15 analogs of benzimidazole based thiadiazole derivatives, which were subsequently confirmed through spectroscopic techniques including (1)H NMR, (13)C NMR and HREI-MS. Biological investigation of all the analogs revealed their varied acetylcholinesterase inhibitory potency covering a range between 3.20 +/- 0.10 microM to 20.50 +/- 0.20 microM as well as butyrylcholinesterase inhibitory potential with a range of 4.30 +/- 0.50 microM to 20.70 +/- 0.50 microM when compared with the standard drug Donepezil having IC(50) = 6.70 +/- 0.20 microM for AChE and 7.90 +/- 0.10 microM for BuChE. The promising inhibition by the analogs was evaluated in SAR analysis, where analog-1 (IC(50) = 3.20 +/- 0.10 microM for AChE and 4.30 +/- 0.50 microM for BuChE), analog-4 (IC(50) = 4.30 +/- 0.30 microM for AChE and 5.50 +/- 0.20 microM for BuChE) and analog-5 (IC(50) = 4.10 +/- 0.30 microM for AChE and 4.60 +/- 0.40 microM for BuChE) were found as the lead candidates. Moreover, molecular docking and ADME analysis were conducted to explore the better binding interactions and drugs likeness respectively.