Phenotypic-based Discovery and Exploration of a Resorufin Scaffold with Activity against Mycobacterium Tuberculosis.

IF 3.6 4区医学 Q2 CHEMISTRY, MEDICINAL

ChemMedChem Pub Date : 2024-09-09 DOI:10.1002/cmdc.202400482

Eric Tran, Lucy Li, Chen-Yi Cheung, Glen P Carter, Robert W Gable, Nicholas P West, Amandeep Kaur, Yi Sing Gee, Gregory Cook, Jonathan B Baell, Manuela Joerg

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Abstract

Tuberculosis remains a leading cause of death by infectious disease. The long treatment regimen and the spread of drug-resistant strains of the causative agent Mycobacterium tuberculosis (Mtb) necessitates the development of new treatment options. In a phenotypic screen, a nitrofuran-resorufin conjugate 1 was identified as a potent sub-micromolar inhibitor of whole cell Mtb. Complete loss of activity was observed for this compound in Mtb mutants affected in enzyme cofactor F420 biosynthesis (fbiC), suggesting that 1 undergoes prodrug activation in a manner similar to anti-tuberculosis prodrug pretomanid. Exploration of the structure-activity relationship led to the discovery of novel resorufin analogues that do not rely on the deazaflavin-dependent nitroreductase (Ddn) bioactivation pathway for their antimycobacterial activity. These analogues are of interest as they work through an alternative, currently unknown mechanism that may expand our chemical arsenal towards the treatment of this devastating disease.

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基于表型发现和探索具有抗结核分枝杆菌活性的 Resorufin 支架。

结核病仍然是传染病致死的主要原因。由于结核分枝杆菌（Mtb）的治疗疗程较长，且耐药菌株不断扩散，因此有必要开发新的治疗方案。在表型筛选中，一种硝基呋喃-resorufin 共轭物 1 被鉴定为对全细胞 Mtb 的亚微摩尔强效抑制剂。在受辅助因子 F420 生物合成酶（fbiC）影响的 Mtb 突变体中，观察到该化合物完全丧失活性，这表明 1 的原药活化方式与抗结核原药 pretomanid 相似。通过对结构-活性关系的研究，发现了新型的间苯二酚类似物，它们的抗霉菌活性不依赖于依赖于硝基还原酶（Ddn）的生物活化途径。这些类似物通过另一种目前未知的机制发挥作用，可能会扩大我们治疗这种毁灭性疾病的化学武库，因此很有意义。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ChemMedChem 医学-药学

CiteScore

6.70

自引率

2.90%

发文量

280

审稿时长

1 months

期刊介绍： Quality research. Outstanding publications. With an impact factor of 3.124 (2019), ChemMedChem is a top journal for research at the interface of chemistry, biology and medicine. It is published on behalf of Chemistry Europe, an association of 16 European chemical societies. ChemMedChem publishes primary as well as critical secondary and tertiary information from authors across and for the world. Its mission is to integrate the wide and flourishing field of medicinal and pharmaceutical sciences, ranging from drug design and discovery to drug development and delivery, from molecular modeling to combinatorial chemistry, from target validation to lead generation and ADMET studies. ChemMedChem typically covers topics on small molecules, therapeutic macromolecules, peptides, peptidomimetics, and aptamers, protein-drug conjugates, nucleic acid therapies, and beginning 2017, nanomedicine, particularly 1) targeted nanodelivery, 2) theranostic nanoparticles, and 3) nanodrugs. Contents ChemMedChem publishes an attractive mixture of: Full Papers and Communications Reviews and Minireviews Patent Reviews Highlights and Concepts Book and Multimedia Reviews.