Ceska Slov Farm. 2021 Fall;70(5):164–171. doi: 10.5817/CSF2021-5-164.
High prevalence and stronger emergency of various forms of drug-resistant tuberculosis (DR-TB), including the multidrug-resistant (MDR-TB) as well as extensively drug-resistant (XDR-TB) ones, caused by variously resistant Mycobacterium tuberculosis pathogens, make first-line anti-tuberculosis (anti-TB) agents therapeutically more and more ineffective. Therefore, there is an imperative to develop novel highly efficient (synthetic) agents against both drug-sensitive-TB and DR-TB. The exploration of various heterocycles as prospective core scaffolds for the discovery, development and optimization of anti-TB drugs remains an intriguing scientific endeavour. Telacebec (Q203; TCB), a molecule containing an imidazo[1,2-a]pyridine-3-carboxamide (IPA) structural motif, is considered a novel very promising anti-TB agent showing a unique mechanism of action. The compound blocks oxidative phosphorylation by inhibiting a mycobacterial respiratory chain due to interference with a specific cytochrome b subunit (QcrB) of transmembrane bc1 menaquinol-cytochrome c oxidoreductase as an essential component for transporting electrons across the membrane from menaquinol to other specific subunit, cytochrome c (QcrC). Thus, the ability of mycobacteria to synthesize adenosine-5´-triphosphate is limited and energy generating machinery is disabled. The TCB molecule effectively fights drug-susceptible, MDR as well as XDR M. tuberculosis strains. The article briefly explains a mechanism of an anti-TB action related to the compounds containing a variously substituted IPA scaffold and is focused on their fundamental structure-anti-TB activity relationships as well. Special consideration is paid to TCB indicating the importance of particular structural fragments for maintaining (or even improving) favourable pharmacodynamic, pharmacokinetic and/or toxicological properties. High lipophilicity of TCB might be regarded as one of the key physicochemical properties with positive impact on anti-TB effect of the drug. In January 2021, the TCB molecule was also involved in phase-II clinical trials focused on the treatment of Coronavirus Disease-19 caused by Severe Acute Respiratory Syndrome Coronavirus 2.
各种形式的耐药结核病（DR-TB），包括耐多药（MDR-TB）和广泛耐药（XDR-TB），其病原体对各种耐药结核分枝杆菌的高流行率和更强的紧急情况，使一线抗结核（anti-TB）药物的治疗效果越来越差。因此，迫切需要开发针对敏感结核和耐药结核的新型高效（合成）药物。探索各种杂环作为发现、开发和优化抗结核药物的潜在核心支架仍然是一项有趣的科学努力。Telacebec（Q203；TCB）是一种含有咪唑并[1,2-a]吡啶-3-甲酰胺（IPA）结构基序的分子，被认为是一种新型非常有前途的抗结核药物，具有独特的作用机制。该化合物通过干扰跨膜 bc1 menaquinol-cytochrome c 氧化还原酶的特定细胞色素 b 亚基（QcrB）来阻断氧化磷酸化，作为将电子从menaquinol 转运到其他特定亚基细胞色素 c（QcrC）的必需组件。因此，分枝杆菌合成腺苷-5´-三磷酸的能力受到限制，能量产生机制被禁用。TCB 分子有效地对抗药物敏感、MDR 甚至 XDR M. tuberculosis 菌株。本文简要解释了与含有各种取代 IPA 支架的化合物相关的抗结核作用机制，并重点介绍了它们的基本结构-抗结核活性关系。特别考虑了 TCB，指出了特定结构片段对于维持（甚至改善）有利的药效学、药代动力学和/或毒理学特性的重要性。TCB 的高亲脂性可能被认为是对药物抗结核作用具有积极影响的关键物理化学特性之一。2021 年 1 月，TCB 分子也参与了针对由严重急性呼吸系统综合症冠状病毒 2 引起的冠状病毒病-19 的 II 期临床试验。
