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We have developed new thiadiazole-containing Schiff base derivatives and examined their ability to inhibit α-amylase and α-glucosidase. Among the members of series, analogue 1 showed excellent inhibitory potential (IC50 = 1.60 ± 0.20 and 2.40 ± 0.10 µM for α-amylase and α-glucosidase) as compare to standard Acarbose (IC50 = 5.30 ± 0.20 and 6.10 ± 0.10 µM). Trifluoromethyl substituted analogue-1 showed best properties because of hydrogen bond formation. Analogue 3 and 9 were also found potent against the target enzymes. All the compounds were investigated for their antibacterial and antifungal activity. Analogue 1, 3 and 9 exhibited bacterial inhibition of 42.3 %, 40.1 %, 38.2 %, and 36.5 %, respectively in contrast to streptomycin (44 %). Analogue 1, 4 and 9 exhibited excellent anti-fungal potency of 43.4, 31.9 and 34.3 %, respectively as compared to standard terinafine (50.6675 %). Scaffolds (1–12) were analyzed through HREI-mass spectrometry, 13C NMR, and 1H NMR. The functioning of active interacting residues for the enzymes was determined by molecular docking (MD), and it was found that thiadiazole bearing Schiff base derivatives could be considered suitable anti-diabetic drugs. ADMET and DFT analysis was also performed to determine stability, drug properties and electronic properties (electrophilic, nucleophilic, HOMO, LUMO) of the synthesized compounds.

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 1H NMR, 13C 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. • Design and target synthesis of novel benzimidazole based thiadiazole derivatives. • Isolated compounds were evaluated for in vitro anti-Alzheimer. • A number of the compounds exhibited excellent activity, few of them shows better than the reference drug. • A molecular docking and ADMET study was used to determine the binding interactions and their toxicity respectively. [ABSTRACT FROM AUTHOR]