硝基咪唑类药物治疗结核病：过去、现在和未来。
Nitroimidazoles for the treatment of TB: past, present and future.
机构信息
Tuberculosis Research Section, LCID, NIAID, NIH, Room 2W20G, Building 33, 9000 Rockville Pike, Bethesda, MD 20892, USA.
出版信息
Future Med Chem. 2011 Sep;3(11):1427-54. doi: 10.4155/fmc.11.90.
Abstract
Tuberculosis remains a leading cause of death resulting from an infectious agent, and the spread of multi- and extensively drug-resistant strains of Mycobacterium tuberculosis poses a threat to management of global health. New drugs that effectively shorten the duration of treatment and are active against drug-resistant strains of this pathogen are urgently required to develop effective chemotherapies to combat this disease. Two nitroimidazoles, PA-824 and OPC-67683, are currently in Phase II clinical trials for the treatment of TB and the outcome of these may determine the future directions of drug development for anti-tubercular nitroimidazoles. In this review we summarize the development of these nitroimidazoles and alternative analogs in these series that may offer attractive alternatives to PA-824 and OPC-67683 for further development in the drug-discovery pipeline. Lastly, the potential pitfalls in the development of nitroimidazoles as drugs for TB are discussed.
摘要
结核病仍然是由感染因子导致的主要死亡原因，而耐多药和广泛耐药结核分枝杆菌菌株的传播对全球卫生管理构成了威胁。迫切需要新的药物来有效缩短治疗时间，并对这种病原体的耐药菌株具有活性，以开发有效的化疗方法来对抗这种疾病。两种硝基咪唑类药物 PA-824 和 OPC-67683 目前正在进行治疗结核病的 II 期临床试验，这些试验的结果可能决定抗结核硝基咪唑类药物的未来药物研发方向。在这篇综述中，我们总结了这些硝基咪唑类药物以及该系列中其他类似物的开发情况，这些类似物可能为 PA-824 和 OPC-67683 提供有吸引力的替代品，以进一步开发药物发现管道。最后，讨论了将硝基咪唑类药物开发为结核病药物的潜在陷阱。
相似文献
1
Nitroimidazoles for the treatment of TB: past, present and future.硝基咪唑类药物治疗结核病：过去、现在和未来。
Future Med Chem. 2011 Sep;3(11):1427-54. doi: 10.4155/fmc.11.90.
2
Delamanid: From discovery to its use for pulmonary multidrug-resistant tuberculosis (MDR-TB).地拉米定：从发现到用于治疗肺部耐多药结核病（MDR-TB）。
Tuberculosis (Edinb). 2018 Jul;111:20-30. doi: 10.1016/j.tube.2018.04.008. Epub 2018 May 3.
3
[Recent progress in mycobacteriology].[分枝杆菌学的最新进展]
Kekkaku. 2007 Oct;82(10):783-99.
4
PA-824 , moxifloxacin and pyrazinamide combination therapy for tuberculosis.PA-824，莫西沙星和吡嗪酰胺联合治疗结核病。
Expert Opin Investig Drugs. 2013 Jul;22(7):927-32. doi: 10.1517/13543784.2013.801958. Epub 2013 May 21.
5
New drugs and new regimens for the treatment of tuberculosis: review of the drug development pipeline and implications for national programmes.新型结核病治疗药物和方案：药物研发管道综述及其对国家规划的影响。
Curr Opin Pulm Med. 2010 May;16(3):186-93. doi: 10.1097/MCP.0b013e328337580c.
6
Delamanid, linezolid, levofloxacin, and pyrazinamide for the treatment of patients with fluoroquinolone-sensitive multidrug-resistant tuberculosis (Treatment Shortening of MDR-TB Using Existing and New Drugs, MDR-END): study protocol for a phase II/III, multicenter, randomized, open-label clinical trial.地拉米胺、利奈唑胺、左氧氟沙星和吡嗪酰胺用于治疗氟喹诺酮敏感的耐多药结核病患者（使用现有和新药缩短耐多药结核病治疗时间，MDR-END）：一项II/III期、多中心、随机、开放标签临床试验的研究方案
Trials. 2019 Jan 16;20(1):57. doi: 10.1186/s13063-018-3053-1.
7
[Development of antituberculous drugs: current status and future prospects].[抗结核药物的研发：现状与未来前景]
Kekkaku. 2006 Dec;81(12):753-74.
8
Bactericidal activity of the nitroimidazopyran PA-824 in a murine model of tuberculosis.硝基咪唑并吡喃类药物PA - 824在小鼠结核病模型中的杀菌活性
Antimicrob Agents Chemother. 2005 Jun;49(6):2289-93. doi: 10.1128/AAC.49.6.2289-2293.2005.
9
New anti-tuberculosis drugs with novel mechanisms of action.具有新型作用机制的新型抗结核药物。
Curr Med Chem. 2008;15(19):1956-67. doi: 10.2174/092986708785132906.
10
Bedaquiline and Delamanid Combination Treatment of 5 Patients with Pulmonary Extensively Drug-Resistant Tuberculosis.贝达喹啉和德拉马尼联合治疗 5 例广泛耐药肺结核患者。
Emerg Infect Dis. 2017 Oct;23(10):1718-21. doi: 10.3201/eid2310.170834. Epub 2017 Oct 17.
引用本文的文献
1
Biocatalytic Strategies for Nitration Reactions.硝化反应的生物催化策略
JACS Au. 2024 Dec 16;5(1):28-41. doi: 10.1021/jacsau.4c00994. eCollection 2025 Jan 27.
2
Novel Prodrug Strategies for the Treatment of Tuberculosis.治疗结核病的新型前药策略。
Chem Asian J. 2024 Dec 2;19(23):e202400944. doi: 10.1002/asia.202400944. Epub 2024 Oct 24.
3
Nitrobenzoates and Nitrothiobenzoates with Activity against .具有抗……活性的硝基苯甲酸酯和硝基硫代苯甲酸酯
Microorganisms. 2023 Apr 8;11(4):969. doi: 10.3390/microorganisms11040969.
4
Functionalized Nitroimidazole Scaffold Construction and Their Pharmaceutical Applications: A 1950-2021 Comprehensive Overview.功能化硝基咪唑支架的构建及其药物应用：1950 - 2021年综述
Pharmaceuticals (Basel). 2022 Apr 30;15(5):561. doi: 10.3390/ph15050561.
5
The adsorption characteristics and degradation mechanism of tinidazole on an anatase TiO surface: a DFT study.替硝唑在锐钛矿型TiO表面的吸附特性及降解机理：一项密度泛函理论研究
RSC Adv. 2020 Jan 10;10(4):2104-2112. doi: 10.1039/c9ra06665a. eCollection 2020 Jan 8.
6
Combining enabling formulation strategies to generate supersaturated solutions of delamanid: In situ salt formation during amorphous solid dispersion fabrication for more robust release profiles.结合使能制剂策略以生成地拉米韦的过饱和溶液：在无定形固体分散体制备过程中进行原位成盐以实现更稳定的释放曲线。
Eur J Pharm Biopharm. 2022 May;174:131-143. doi: 10.1016/j.ejpb.2022.04.002. Epub 2022 Apr 9.
7
MDR Tuberculosis Treatment.耐多药结核病治疗。
Medicina (Kaunas). 2022 Jan 26;58(2):188. doi: 10.3390/medicina58020188.
8
Overcoming the Prokaryote/Eukaryote Barrier in Tuberculosis Treatment: A Prospect for the Repurposing and Use of Antiparasitic Drugs.克服结核病治疗中的原核生物/真核生物障碍：抗寄生虫药物重新利用和使用的前景。
Microorganisms. 2021 Nov 11;9(11):2335. doi: 10.3390/microorganisms9112335.
9
Mechanism of Action, Resistance, Synergism, and Clinical Implications of Delamanid Against Multidrug-Resistant .地拉米韦对多重耐药菌的作用机制、耐药性、协同作用及临床意义
Front Microbiol. 2021 Oct 7;12:717045. doi: 10.3389/fmicb.2021.717045. eCollection 2021.
10
New Antibiotics for Multidrug-Resistant Bacterial Strains: Latest Research Developments and Future Perspectives.多药耐药菌新抗生素：最新研究进展及未来展望。
Molecules. 2021 May 2;26(9):2671. doi: 10.3390/molecules26092671.
本文引用的文献
1
The nitroimidazooxazines (PA-824 and analogs): structure-activity relationship and mechanistic studies.硝咪唑嗪类化合物（PA-824 及其类似物）：结构-活性关系和机制研究。
Future Med Chem. 2010 Aug;2(8):1295-304. doi: 10.4155/fmc.10.207.
2
Maximizing bactericidal activity with combinations of bioreduced drugs.用生物还原药物的组合来最大限度地提高杀菌活性。
Future Med Chem. 2010 Aug;2(8):1253-71. doi: 10.4155/fmc.10.215.
3
High-sensitivity MALDI-MRM-MS imaging of moxifloxacin distribution in tuberculosis-infected rabbit lungs and granulomatous lesions.高灵敏度 MALDI-MRM-MS 成像技术研究莫西沙星在感染结核分枝杆菌的兔肺组织和肉芽肿病变中的分布
Anal Chem. 2011 Mar 15;83(6):2112-8. doi: 10.1021/ac1029049. Epub 2011 Feb 18.
4
The effect of 5-substitution on the electrochemical behavior and antitubercular activity of PA-824.5-取代基对 PA-824 的电化学行为和抗结核活性的影响。
Bioorg Med Chem Lett. 2011 Jan 15;21(2):812-7. doi: 10.1016/j.bmcl.2010.11.093. Epub 2010 Nov 25.
5
Synthesis and structure-activity relationships of aza- and diazabiphenyl analogues of the antitubercular drug (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824).氮杂和二氮杂联苯类似物的合成及结构活性关系，该类似物为抗结核药物（6S）-2-硝基-6-[[4-（三氟甲氧基）苄基]氧基]-6,7-二氢-5H-咪唑并[2,1-b][1,3]恶嗪（PA-824）。
J Med Chem. 2010 Dec 9;53(23):8421-39. doi: 10.1021/jm101288t. Epub 2010 Nov 11.
6
Early bactericidal activity and pharmacokinetics of PA-824 in smear-positive tuberculosis patients.PA-824 在涂阳肺结核患者中的早期杀菌活性和药代动力学。
Antimicrob Agents Chemother. 2010 Aug;54(8):3402-7. doi: 10.1128/AAC.01354-09. Epub 2010 May 24.
7
Clinical tuberculosis and treatment outcomes.临床结核病与治疗结果。
Int J Tuberc Lung Dis. 2010 Jun;14(6):683-8.
8
Dry powder PA-824 aerosols for treatment of tuberculosis in guinea pigs.干粉 PA-824 气溶胶治疗豚鼠结核病。
Antimicrob Agents Chemother. 2010 Apr;54(4):1436-42. doi: 10.1128/AAC.01471-09. Epub 2010 Jan 19.
9
Synthesis and structure-activity relationships of antitubercular 2-nitroimidazooxazines bearing heterocyclic side chains.含杂环侧链的抗结核 2-硝基咪唑恶嗪的合成及构效关系。
J Med Chem. 2010 Jan 28;53(2):855-66. doi: 10.1021/jm901378u.
10
An anaerobic-type alpha-ketoglutarate ferredoxin oxidoreductase completes the oxidative tricarboxylic acid cycle of Mycobacterium tuberculosis.一种厌氧型 α-酮戊二酸铁氧还蛋白氧化还原酶完成结核分枝杆菌的氧化三羧酸循环。
PLoS Pathog. 2009 Nov;5(11):e1000662. doi: 10.1371/journal.ppat.1000662. Epub 2009 Nov 20.
Zotero 插件