Benzothiazole-driven molecular probes and therapeutics for neurodegenerative diseases: focus on amyloid-beta (Aβ), tau, and α-synuclein.

Abstract

Neurodegenerative disorders, particularly Alzheimer's disease (AD) and Parkinson's disease (PD), represent a rapidly growing global health challenge characterized by progressive neuronal loss, irreversible cognitive decline, and the absence of effective disease-modifying therapies. A major obstacle in the clinical management of these disorders is the inability to accurately diagnose pathological changes at early stages, when therapeutic intervention is most likely to be effective. The pathological aggregation of amyloid-β (Aβ), hyperphosphorylated tau, and α-synuclein (α-syn) constitutes a central molecular hallmark of neurodegeneration and has therefore emerged as a critical target for both diagnostic imaging and therapeutic intervention. Among the numerous heterocyclic scaffolds investigated for central nervous system drug discovery, benzothiazole (BZT) has attracted exceptional attention owing to its favorable blood-brain barrier permeability, synthetic versatility, and intrinsic affinity toward β-sheet-rich protein aggregates. The clinical success of Pittsburgh compound-B (PiB) established BZT as a privileged molecular recognition motif for in vivo visualization of amyloid pathology and stimulated extensive medicinal chemistry efforts toward the development of next-generation imaging probes. More recently, advances in structure-guided design and multitarget-directed ligand (MTDL) strategies have transformed BZT from a purely diagnostic scaffold into a versatile theranostic platform capable of simultaneously recognizing and modulating neurodegenerative proteinopathies. Between 2020 and 2026, a wide range of structurally diverse BZT-based derivatives and hybrid molecules have been reported with improved affinity, selectivity, and sensitivity toward Aβ plaques, tau fibrils, and α-synuclein aggregates, while also exhibiting therapeutic activities such as inhibition of protein aggregation, fibril destabilization, cholinesterase inhibition, monoamine oxidase modulation, antioxidant activity, metal chelation, mitochondrial protection, and neuroinflammation suppression. This review provides a comprehensive overview of recent advances (2020-2026) in the design, synthesis, structure-activity relationships, molecular mechanisms, diagnostic applications, and therapeutic potential of BZT-based agents for neurodegenerative disorders. Particular emphasis is placed on the molecular basis of BZT recognition of amyloidogenic proteins, the evolution of diagnostic probes into multifunctional therapeutic hybrids, and emerging theranostic strategies targeting interconnected pathological pathways associated with AD, PD, and related proteinopathies. Furthermore, key trends in medicinal chemistry, translational challenges, and future opportunities for the development of next-generation BZT-derived diagnostics and therapeutics are critically discussed. Collectively, the evidence highlights BZT as one of the most promising privileged scaffolds for integrating early diagnosis, disease monitoring, and disease-modifying intervention within a unified molecular framework for neurodegenerative disorders.