Hybrid benzothiazole derived fused triazole/thiazole derivatives as versatile anti-Alzheimer agents: synthesis, characterization, biological evaluation and molecular docking studies.

• Synthesis and spectroscopic techniques of hybrid benzothiazole derived fused triazole/thiazole derivatives. • Isolated compounds were evaluated for in vitro anti-Alzheimer activity. • A number of the compounds exhibited excellent activity, some better than the reference standards. • A molecular docking and ADMET studies were used to determine the binding interactions of the potent compounds with the enzymes active sites and their toxicity respectively. Alzheimer's disease, as per reports, 50 million people worldwide suffer from dementia and an increase of 152 million is expected by 2050. This study reports a novel synthetic approach to designing and synthesizing a series of benzothiazole-based fused 1,3,4-triazole/1,3,4-thiadiazole hybrid derivatives (1–19), which show promising potential as therapeutic agents for the treatment of Alzheimer's disease. These derivatives were structurally confirmed through spectroscopic analytical techniques, including 13C NMR, 1H NMR and HREI-MS. All the analogs were subjected to biological inhibitory evaluation against AChE and BuChE, in which analog 2 ((IC 50 = 3.30 ± 0.20 and 3.70 ± 0.40 µM), 7 (2.70 ± 0.10 and 3.240 ± 0.10 µM), 12 (4.80 ± 0.30 and 5.40 ± 0.20 µM), 15 (2.10 ± 0.20 and 3.10 ± 0.50 µM) and 19 (4.40 ± 0.20 and 5.10 ± 0.10 µM)) exhibited spellbinding potency in contrast to standard Donepezil (IC 50 = 4.60 ± 0.10 µM for AChE and 5.20 ± 0.71 µM for BuChE). The surpassing potential of the analogs is elaborated in SAR analysis, based on number, position and nature of the substituents. In this regard, analog 15 having two flouro groups, was found as the top ranking candidate, inhibiting the enzymes through hydrogen bonding. Additionally, molecular docking study was also performed to investigate the binding modes and interactions between the ligands and the target protein. Furthermore, the drug-likeness of the compounds was evaluated through in silico ADME analysis, which assessed their pharmacokinetic properties and potential to become a successful drug candidate. [ABSTRACT FROM AUTHOR]