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    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 (IC50 = 0.03 μM) and 464-fold selectivity over MAO-A, compared to the standard drugs Pargyline (IC50 = 0.14 μM) and Clorgyline (IC50 = 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. © 2024 American Chemical Society.

    Citation

    Mayur S Dhangar, Iqrar Ahmad, Jong Min Oh, Bhatu R Patil, Sampath Chinnam, Dharmarajan Sriram, Jyothi Kumari, Bijo Mathew, Rais A Sayyed, Shubham B Chaudhari, Siddique Akber Ansari, Nishant Rai, Hoon Kim, Harun M Patel. Optimizing Linezolid: Transforming It into a Selective MAO-B Inhibitor via a Toxicity-to-Activity Optimization Approach. ACS medicinal chemistry letters. 2025 Jan 09;16(1):40-50


    PMID: 39811132

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