Benzothiazole-Based Polyfunctional Agents in Alzheimer’s Therapy: Dual Diagnostic and Therapeutic Targeting of Aβ, Tau, and Neuroinflammation
TL;DR
The benzothiazole-derived polyfunctional compounds move in a direction that calls for speedy translation research towards the development of disease-modifying agents in AD, and challenges in off-target binding affinity, metabolic instability, Pglycoprotein efflux susceptibility, and the lack of in vivo studies in the long term emphasise the need for lead optimisation strategies.
Abstract
Alzheimer's disease is known to be a multifaceted neurodegenerative disease, which includes events like amyloid-β (Aβ) plaque deposition, tau protein hyperphosphorylation, oxidative damage, neuroinflammation, and cholinergic dysfunction, for which the conventional pharmacotherapies only bring temporary symptomatic relief. Benzothiazoles are known to be novel polyfunctional agents, acting as multi-target directed ligands, owing to their privileged heterocyclic structure, making it more feasible to accomplish combined antioxidant, anti-amyloidogenic, cholinesterase, and anti-inflammatory activities, together with optimal blood-brain barrier penetration and lipophilicity. The review systematically recapitulates progress, ranging from benzothiazole synthesis using efficient cyclocondensation techniques with o-aminothiophenols to SAR investigations focusing on C-2 aryl/heteroaromatic substituents to increase enzyme inhibition efficacy, as well as modulation of Aβ/tau aggregation with IC50 values of 0.15 to 1.2 μM, to pharmacological profiling of novel hybrids carrying a pharmacophore. In preclinical studies, the results of these multifunctional derivatives confirm their potential superiority over single-target agents, such as donepezil, in possessing dual AChE/BChE inhibition, GSK-3β/CDK5 kinase inhibition, potent ROS-scavenging activity (up to 45% inhibition at 10 μM concentration), and pro-inflammatory cytokine reduction in microglial cells. Although the multitarget interaction properties of these derivatives in the context of AD pathologies appear highly persuasive, challenges in off-target binding affinity, metabolic instability, Pglycoprotein efflux susceptibility, and the lack of in vivo studies in the long term emphasise the need for lead optimisation strategies. Indeed, the benzothiazole-derived polyfunctional compounds move in a direction that calls for speedy translation research towards the development of disease-modifying agents in AD.