Structural toxicity relationship (STR) of linezolid to mitigate myelosuppression and serotonergic toxicity

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry Pub Date : 2024-11-29 DOI:10.1016/j.bmc.2024.118025

Matin Shaikh , Harun Patel

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Abstract

Tuberculosis (TB) remains a significant global health challenge, with multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) strains posing severe threats to treatment efficacy. Linezolid, a key component of the BPaL (Bedaquiline, Pretomanid and Linezolid) regimen, has demonstrated substantial efficacy against MDR-TB and XDR-TB. However, its clinical utility is often limited by side effects such as myelosuppression and monoamine oxidase (MAO) inhibition, linked to its mechanism of action. This perspective centres on the structural toxicity relationship (STR) of Linezolid and its analogues, exploring modifications to the C-ring and C-5 position that aim to reduce these toxicities while maintaining or enhancing antibacterial activity. Several promising analogues have been identified that exhibit reduced myelosuppression and MAO inhibition, highlighting the potential for developing safer Linezolid derivatives. The findings underscore the importance of continued research into the structure toxicity relationships of oxazolidinones to improve the therapeutic profiles of these essential drugs in combating drug-resistant TB.

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利奈唑胺减轻骨髓抑制和血清素能毒性的结构毒性关系

结核病（TB）仍然是一个重大的全球卫生挑战，耐多药（MDR-TB）和广泛耐药（XDR-TB）菌株对治疗效果构成严重威胁。利奈唑胺是BPaL（贝达喹啉、普雷托马尼和利奈唑胺）方案的关键组成部分，已证明对耐多药结核病和广泛耐药结核病具有显著疗效。然而，它的临床应用往往受到副作用的限制，如骨髓抑制和单胺氧化酶（MAO）抑制，这与它的作用机制有关。这一观点集中在利奈唑胺及其类似物的结构毒性关系（STR）上，探索对c环和C-5位置的修饰，旨在降低这些毒性，同时保持或增强抗菌活性。已经确定了几种有前途的类似物，它们表现出减少骨髓抑制和MAO抑制，突出了开发更安全的利奈唑胺衍生物的潜力。这些发现强调了继续研究恶唑烷酮的结构毒性关系以改善这些基本药物在对抗耐药结核病中的治疗概况的重要性。

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来源期刊

Bioorganic & Medicinal Chemistry 医学-生化与分子生物学

CiteScore

6.80

自引率

2.90%

发文量

413

审稿时长

17 days

期刊介绍： Bioorganic & Medicinal Chemistry provides an international forum for the publication of full original research papers and critical reviews on molecular interactions in key biological targets such as receptors, channels, enzymes, nucleotides, lipids and saccharides. The aim of the journal is to promote a better understanding at the molecular level of life processes, and living organisms, as well as the interaction of these with chemical agents. A special feature will be that colour illustrations will be reproduced at no charge to the author, provided that the Editor agrees that colour is essential to the information content of the illustration in question.