Recent advances in the development of selective hMAO-B inhibitors for neurodegenerative diseases: An update from 2020 to present

Neurodegenerative diseases (NDs) comprise a complex group of disorders characterized by the progressive loss of neurons in the CNS, resulting in cognitive and motor dysfunctions. Elucidating the molecular mechanisms underlying these diseases is essential to identify effective therapeutic strategies. The hallmarks of NDs include oxidative stress, mitochondrial dysfunction, neuroinflammation, and protein misfolding. Among the implicated molecular targets, monoamine oxidase B (MAO-B) plays a crucial role since it catalyzes the oxidative deamination of biogenic amines, such as amine neurotransmitters, and therefore plays an important role in the physiopathology of the brain and nervous system generating reactive oxygen species, so contributing to oxidative stress and inflammation. Elevated hMAO-B activity has been observed in Alzheimer's and Parkinson's disease, underscoring its potential as a therapeutic target for neuroprotection. Given the role of MAO-B activity in various molecular pathways related to neuroinflammatory and neurodegenerative processes that underlie the onset and progression of NDs, the development of more active and selective hMAO-B inhibitors could represent a promising avenue leading to safer and more effective therapies for Alzheimer's and Parkinson's disease. In this view, MAO-B inhibitors have long been investigated for their therapeutic potential in NDs. Building upon previous reviews, this updated overview focuses on the most recent advances from 2020 to today in the field of new small molecules hMAO-B inhibitors, highlighting results from preclinical studies. Attention is paid to the various classes of synthetic compounds that have emerged in recent years and, where available, the main structure-activity relationships (SARs) are discussed to provide insights into the molecular features responsible for hMAO-B inhibitory activity and selectivity. The aim is to provide researchers with a current perspective on the evolving landscape of hMAO-B inhibitor-based therapies for NDs.