Novel approaches to the discovery of selective human monoamine oxidase-B inhibitors: is there room for improvement?

ABSTRACT

Introduction: Selective monoamine oxidase-B (MAO-B) inhibitors are currently used as coadjuvants for the treatment of early motor symptoms in Parkinson’s disease. They can, based on their chemical structure and mechanism of inhibition, be categorized into reversible and irreversible agents.

Areas covered: This review provides a comprehensive update on the development state of selective MAO-B inhibitors describing the results, structures, structure–activity relationships (SARs) and Medicinal chemistry strategies as well as the related shortcomings over the past five years.

Expert opinion: Researchers have explored and implemented new and old chemical scaffolds achieving high inhibitory potencies and isoform selectivity. Most of them were characterized and proposed as multitarget agents able to act at different levels (including AChE inhibition, H3R or A_2AR antagonism, antioxidant and chelating properties, Aβ_1-42 aggregation reduction) in the network of aetiologies of neurodegenerative disorders. These results can also be used to avoid ‘cheese-reaction’ effects and the occurrence of serotonergic syndrome in patients.

KEYWORDS:

• Benzyloxy
• coumarins
• flavonoids
• monoamine oxidase B inhibitors
• oxazolidinones
• pyrazolines
• thiosemicarbazones

Article highlights

• Selective MAO-B inhibitors can be used for the treatment of neurodegenerative disorders avoiding ‘cheese-reaction’ effect in patients.

• ‘one molecule-multi target’ paradigm is the new frontier for the development of efficacious protocols.

• Old and new scaffolds were further developed in terms of inhibitory potency, isoform selectivity, ADME parameters, and limited cytotoxicity.

• New therapeutic options have been described for selective MAO-B inhibitors with particular emphasis on cancer.

• A large plethora of efforts have been made in the design and synthesis of selective MAO-B inhibitors in the last five years, thus demonstrating the importance and the main role of this target.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript has not been funded.