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

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL ACS Medicinal Chemistry Letters Pub Date : 2024-12-16 eCollection Date: 2025-01-09 DOI:10.1021/acsmedchemlett.4c00354

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

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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 (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.

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.