This broad review highlights benzimidazole as a versatile medicinal chemistry scaffold with preclinical MAO-B inhibitors, dopamine receptor modulators, and NMDA antagonists and reports favourable ADMET/BBB properties, but provides limited PD-specific in vivo or clinical evidence.

For Parkinson’s drug discovery, benzimidazole derivatives offer actionable repurposing and multi-target opportunities (MAO-B inhibition, dopaminergic modulation, anti-excitotoxic and anti-aggregation strategies) that warrant focused in vivo PD studies and optimization toward clinical candidates.

Neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) are characterized by progressive neuronal loss, leading to severe cognitive and motor dysfunction. Benzimidazole, a privileged heterocyclic scaffold, has emerged as a promising pharmacophore in modulating key pathological targets across these disorders. In AD, benzimidazole derivatives inhibit cholinesterases, glycogen synthase kinase-3β (GSK-3β), and glutaminyl cyclase (QC), thereby addressing cholinergic dysfunction, tau phosphorylation, and amyloid aggregation. In PD and HD, they act as monoamine oxidase-B (MAO-B) inhibitors, dopamine D1/D2 receptor modulators, and N-methyl D-aspartate receptor antagonists, improving dopaminergic signalling and reducing excitotoxicity. In ALS, benzimidazoles regulate acetylcholine dysfunction and inhibit receptor-interacting protein kinase 1 (RIPK1), limiting neuroinflammation and cell death. Preclinical studies demonstrate potent enzyme inhibition, often with IC50 values in the nanomolar to micromolar range, alongside favourable ADMET properties enabling blood-brain barrier penetration. Clinically, the glutaminyl cyclase inhibitor Varoglutamstat has advanced to Phase II trials for AD, while Riluzole remains the only food and drug administration (FDA)-approved benzimidazole drug for ALS. The structural versatility of benzimidazoles supports their development as multi-target-directed ligands, addressing overlapping mechanisms such as protein aggregation, oxidative stress, and neuroinflammation. Emerging strategies including hybrid molecules, nanocarrier delivery, and AI-driven design may accelerate their clinical translation.