Kim Pilho, Zhang Liang, Manjunatha Ujjini H, Singh Ramandeep, Patel Sejal, Jiricek Jan, Keller Thomas H, Boshoff Helena I, Barry Clifton E, Dowd Cynthia S
Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
J Med Chem. 2009 Mar 12;52(5):1317-28. doi: 10.1021/jm801246z.
The 4-nitroimidazole PA-824 is active against aerobic and anaerobic Mycobacterium tuberculosis (Mtb) while 5-nitroimidazoles like metronidazole are active against only anaerobic Mtb. We have synthesized analogues of both 4- and 5-nitroimidazoles and explored their antitubercular activities. The nitro group is required for both activities in all compounds. The key determinants of aerobic activity in the 4-nitroimidazoles include the bicyclic oxazine, the lipophilic tail, and the 2-position oxygen. For the 5-nitroimidazoles, neither the corresponding bicyclic analogue nor addition of a lipophilic tail conveyed aerobic activity. Incorporation of a 2-position oxygen atom into a rigid 5-nitroimidazooxazine provided the first 5-nitroimidazole with aerobic activity. Across both series, anaerobic and aerobic activities were not correlated and Mtb mutants lacking the deazaflavin-dependent nitroreductase (Ddn) retained anaerobic sensitivity to some compounds. Aerobic activity appears to be correlated with efficiency as a substrate for Ddn, suggesting a means of structure-based optimization of improved nitroimidazoles.
4-硝基咪唑类药物PA-824对需氧和厌氧结核分枝杆菌（Mtb）均有活性，而像甲硝唑这样的5-硝基咪唑类药物仅对厌氧Mtb有活性。我们合成了4-硝基咪唑类和5-硝基咪唑类的类似物，并探究了它们的抗结核活性。所有化合物的这两种活性都需要硝基。4-硝基咪唑类药物需氧活性的关键决定因素包括双环恶嗪、亲脂性尾部和2位氧原子。对于5-硝基咪唑类药物，相应的双环类似物和亲脂性尾部的添加均未赋予其需氧活性。将2位氧原子引入刚性5-硝基咪唑并恶嗪中，得到了首个具有需氧活性的5-硝基咪唑类药物。在这两个系列中，厌氧活性和需氧活性不相关，缺乏脱氮黄素依赖性硝基还原酶（Ddn）的Mtb突变体对某些化合物仍保留厌氧敏感性。需氧活性似乎与作为Ddn底物的效率相关，这为基于结构优化改进的硝基咪唑类药物提供了一种方法。
