Thiazole-based Small Molecules as Potential Anti-Alzheimer's Agents: SAR and Mechanistic Insights.

Abstract

A progressive neurodegenerative disease, Alzheimer's Disease (AD), is typified by cognitive decline, synaptic malfunction, and permanent death of neurons. It has a complicated etiology that includes oxidative stress, neuroinflammatory cascades, and monoamine oxidase dysregulation; therapies are limited in their long-term efficacy. This highlights the necessity for carefully crafted multi-target medicines that can modulate multiple pathogenic pathways at once. The advantageous electronic characteristics and structural flexibility of thiazole and benzothiazole derivatives make them appealing, as they can penetrate the blood-brain barrier and serve as heterocyclic scaffolds in medicinal chemistry. According to recent studies, thiazole-based drugs have a strong inhibitory effect against butyrylcholinesterase and acetylcholinesterase, increasing the availability of acetylcholine in synapses. Monoamine oxidase-B (MAO-B) is also strongly and selectively inhibited by several derivatives, which helps to lower oxidative stress and promote neuroprotection. Significantly affecting enzyme affinity, selectivity, and multitarget engagement are structural alterations such as halogen substitution, methoxy incorporation, hydrazone connections, and sulfonamide or piperazine moieties. Beyond enzyme modulation, thiazole-containing molecules interfere with Aβ aggregation, disrupt β-sheet fibril formation, and demonstrate antioxidant and metal-chelating properties. These combined biological effects position thiazole derivatives as potentially disease-modifying multitarget- directed ligands. According to an analysis of the evaluated research, the most effective anti- Alzheimer effects were found in thiazole and benzothiazole derivatives with halogen, methoxy, hydrazone, piperazine, and sulfonamide substituents. Many substances showed nanomolar to low micromolar inhibition of AChE, BuChE, and MAO-B while concurrently inhibiting oxidative stress and amyloid-β formation. Studies on the structure-activity link have shown how crucial strategic substitution patterns are for improving potency, selectivity, and multitarget engagement. This research highlights the feasibility of using thiazoles as scaffold pharmacophores for developing novel drugs to treat Alzheimer's disease and provides vital guidance on the development of future drugs. This review is a comprehensive compilation of small thiazoles being studied for AD with emphasis on structure-activity relationships, molecular targets, and multitarget therapies. This review provides useful information for the rational design of next-generation anti-Alzheimer drugs. It highlights prospective directions for future drug discovery research by methodically outlining current achievements in thiazole-derived AChE, BuChE, MAO-B, and amyloid-β inhibitors.