Design and Synthesis of the Linezolid Bioisosteres to Resolve the Serotonergic Toxicity Associated with Linezolid

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2024-05-20 DOI:10.1021/acsmedchemlett.4c00114

Rukaiyya T. Girase, Iqrar Ahmad, Jong Min Oh, Bijo Mathew, Siva K. Vagolu, Tone Tønjum, Dharmarajan Sriram, Jyothi Kumari, Nisheeth C. Desai, Yogesh Agrawal, Hoon Kim* and Harun M. Patel*,

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Abstract

Serotonergic toxicity due to MAO enzyme inhibition is a significant concern when using linezolid to treat MDR-TB. To address this issue, we designed linezolid bioisosteres with a modified acetamidomethyl side chain at the C-5 position of the oxazolidine ring to balance activity and reduce toxicity. Among these bioisosteres, R7 emerged as a promising candidate, demonstrating greater effectiveness against M. tuberculosis (Mtb) H₃₇Rv cells with an MIC of 2.01 μM compared to linezolid (MIC = 2.31 μM). Bioisostere R7 also exhibited remarkable activity (MIC₅₀) against drug-resistant Mtb clinical isolates, with values of 0.14 μM (INH^R, inhA+), 0.53 μM (INH^R, katG+), 0.24 μM (RIF^R, rpoB+), and 0.92 μM (INH^R INH^R, MDR). Importantly, it was >6.52 times less toxic as compared to the linezolid toward the MAO-A and >64 times toward the MAO-B enzyme, signifying a substantial improvement in its drug safety profile.

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设计和合成利奈唑胺生物异构体，解决利奈唑胺的血清素能毒性问题

在使用利奈唑胺治疗 MDR-TB 时，MAO 酶抑制导致的血清素能毒性是一个重大问题。为了解决这个问题，我们设计了利奈唑胺生物异构体，在恶唑烷环的 C-5 位上添加了经过修饰的乙酰胺甲基侧链，以平衡活性并降低毒性。在这些生物异构体中，R7 是一种很有前途的候选物质，与利奈唑胺（MIC = 2.31 μM）相比，它对结核杆菌（Mtb）H37Rv 细胞更有效，MIC 为 2.01 μM。Bioisostere R7 对耐药的 Mtb 临床分离株也具有显著的活性（MIC50），分别为 0.14 μM（INHR，inhA+）、0.53 μM（INHR，katG+）、0.24 μM（RIFR，rpoB+）和 0.92 μM（INHR INHR，MDR）。重要的是，它对 MAO-A 的毒性是利奈唑胺的 6.52 倍，对 MAO-B 的毒性是利奈唑胺的 64 倍，这表明它的药物安全性大大提高。

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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.