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Optimizing Linezolid: Transforming It into a Selective MAO-B Inhibitor via a Toxicity-to-Activity Optimization Approach

Year: 2024

Type: article

Abstract: Linezolid, a widely used oxazolidinone antibiotic, exhibits potent activity against resistant bacterial infections but is associated with serotonergic toxicity, primarily due to its inhibition of monoamine oxidase (MAO). MAOs, consisting of MAO-A and MAO-B isoforms, play crucial roles in neurotransmitter metabolism, with implications for neurodegenerative disorders like Parkinson’s and Alzheimer’s diseases. This study aims to optimize Linezolid’s structure to transform it into a selective MAO-B inhibitor. Utilizing structure–activity and structure–toxicity relationship approaches, novel analogues of Linezolid were synthesized by replacing its oxazolidinone ring with a thiadiazole scaffold. Among the synthesized compounds, 6b emerged as a lead candidate, displaying a remarkable MAO-B inhibitory activity (IC 50 = 0.03 μM) and 464-fold selectivity over MAO-A, compared to the standard drugs Pargyline (IC 50 = 0.14 μM) and Clorgyline (IC 50 = 1.85 μM). Furthermore, docking and molecular dynamics simulations corroborated the high affinity and stability of compound 6b in the MAO-B enzyme’s binding pocket. These findings suggest that optimized Linezolid analogues, particularly compound 6b, hold promise as selective MAO-B inhibitors, offering therapeutic potential for treating neurodegenerative diseases while avoiding the risks associated with serotonergic toxicity.

Source: ACS Medicinal Chemistry Letters

DOI: 10.1021/acsmedchemlett.4c00354