Background: Parkinson’s disease (PD) is a progressive neurodegenerative disorder with substantial socioeconomic impact, characterized by the gradual loss of dopaminergic neurons, dopamine deficiency, and pathological processes such as neuroinflammation, oxidative stress, and α-synuclein aggregation. Monoamine oxidases (MAOs) are enzymes responsible for the degradation of neuroactive amines, including dopamine, a neurotransmitter essential for motor, cognitive, and behavioral functions. Among these, MAO-B plays a central role in dopamine metabolism, producing reactive metabolites and oxidative species that contribute to the oxidative stress associated with PD pathophysiology. In this context, MAO-B inhibition has emerged as a promising therapeutic strategy. However, specific limitations, such as motor complications linked to prolonged levodopa use and the adverse effects of currently available MAO inhibitors, remain significant clinical challenges. Methods: A comprehensive literature search was conducted using PubMed and SciFinder databases. Keywords such as “MAO inhibitors”, “Parkinson’s pathology,” and “Parkinson’s disease” were combined with Boolean operators (AND, OR, NOT). The search covered publications from 2010 to 2025. Results: While previous reviews, particularly those by the groups of Guglielmi and Alborghetti, mainly emphasized the clinical use of MAO-B inhibitors and advances in patents, the present review identified approximately 300 compounds synthesized and evaluated as MAO inhibitors, encompassing diverse chemical classes. Among them, selective MAO-B inhibitors exhibited the greatest pharmacological potential, reinforcing the relevance of this isoform as a strategic target in PD therapy. Conclusion: These findings highlight the advances of Medicinal Chemistry in the development of novel MAO-B inhibitors, both as monotherapies for early-stage PD and as adjuvants to levodopa in advanced disease. Collectively, they emphasize the promise of MAO-B inhibitors as candidates for more effective therapeutic interventions in Parkinson’s disease.

Parkinson's disease (PD) is a progressive neurodegenerative disease whose symptoms include tremors, gastrointestinal and motor disorders, bradykinesia, depression, sleep disorders, and pain. Currently, after Alzheimer’s Disease, PD is the second most common ND worldwide, with great socioeconomic impact, as it affects people of working age, slowly progresses to a disability, and dementia, remaining incurable to date. The PD pathophysiology is complex and multifactorial, characterized by a progressive loss of dopaminergic neurons, and dopamine deficits, especially in regions of the central nervous system (CNS) related to motor skills and coordination. In addition, the literature is rich in data that suggests the deposition of poorly processed α-synuclein protein fragments, which generate fibril aggregates, known as Lewy’s bodies, into the neuronal cytosol, besides reduced dopamine availability, neuroinflammation, and oxidative stress (OS). The clinical management of PD remains a challenge, with a limited available drug arsenal, low efficacy and the occurrence of tolerance in most cases, requiring the practice of polypharmacology to address the different stages of the disease, including antidepressants and anxiolytics. PD, like other NDs, has a very complex pathogenesis, still not fully understood, given its multifactoriality and the concomitant and interconnected dysfunction of several biochemical pathways and cellular events. In this context, among the diverse molecular targets studied for potential modulation and most effective pharmacological intervention, monoamine oxidase (MAO) isoforms A and B, especially MAO-B, have attracted special attention from the scientific community. This work aims to review the most recent data in the literature regarding the role of MAO in the PD pathophysiology, and the Medicinal Chemistry advances in identifying MAO inhibitors as new drug candidates against PD.