Click Chemistry-Aided Synthesis of Triazole-Tethered Benzothiazoles as Novel Multifunctional Agents Against Alzheimer's Disease

In the current medical era, Alzheimer's disease (AD) stands as a challenging multifaceted neurodegenerative disorder characterized by diverse pathological features that necessitate the development of multi-target directed ligands (MTDLs) as a promising therapeutic approach. This study reports the design and synthesis of triazole-tethered benzothiazole derivatives (10a-r and 11a-e) as MTDLs for AD. These molecules have been evaluated for their potential to inhibit cholinesterases, amyloid-β (Aβ) aggregation, and their reactive oxygen species (ROS) scavenging ability. Benzothiazoles 10f, 10l, and 11c exhibited good inhibition of human acetylcholinesterase (hAChE) with IC₅₀ values of 100, 110, and 140 nM, respectively, and were better than tacrine (IC₅₀ = 160 nM). Furthermore, they inhibited Aβ42 aggregation with percent inhibition of 49.4%, 45.1%, and 39.3%, respectively. It should be emphasized that the most potent hAChE and Aβ42 dual inhibitors, 10f and 10l, displayed efficient antioxidant activities (57.2% and 47.5%, respectively) and were better than resveratrol (40.8%). Noteworthy, the developed molecules were not cytotoxic to mouse hippocampal neuronal cells (HT22) at 25 µM, with cell viability ranging from 79.2% to 113.3%, highlighting their potential to be considered as novel scaffolds for CNS drug development. A molecular docking study proposed that 10f and 10l interacted with both the catalytic and peripheral active sites of hAChE similar to donepezil and displayed favorable binding. Also, the docking study suggested the binding mode of 10f to Aβ40 and Aβ42. These results show that benzothiazoles 10f and 10l are promising candidates for the development of novel MTDLs for the effective management of AD.