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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 μM to 20.50 ± 0.20 μM as well as butyrylcholinesterase inhibitory potential with a range of 4.30 ± 0.50 μM to 20.70 ± 0.50 μM when compared with the standard drug Donepezil having IC 50  = 6.70 ± 0.20 μM for AChE and 7.90 ± 0.10 μM for BuChE. The promising inhibition by the analogs was evaluated in SAR analysis, where analog-1 (IC 50  = 3.20 ± 0.10 μM for AChE and 4.30 ± 0.50 μM for BuChE), analog-4 (IC 50  = 4.30 ± 0.30 μM for AChE and 5.50 ± 0.20 μM for BuChE) and analog-5 (IC 50  = 4.10 ± 0.30 μM for AChE and 4.60 ± 0.40 μM 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., Competing Interests: Declaration of competing interest It is declared that there is no conflict of interest between the authors of the current manuscripts and it is only submitting to Biochemical and Biophysical Research Communication and not submitted elsewhere., (Copyright © 2024 Elsevier Inc. All rights reserved.)