Bactericidal Activity of an Imidazo[1, 2-a]pyridine Using a Mouse M. tuberculosis Infection Model
Bactericidal Activity of an Imidazo[1, 2-a]pyridine Using a Mouse M. tuberculosis Infection Model
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DOI：
10.1371/journal.pone.0087483
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发表时间：
2014-01-31
期刊：
影响因子：
3.7
通讯作者：
Schorey, Jeffrey S.
中科院分区：
文献类型：
--
作者：
Cheng, Yong;Moraski, Garrett C.;Schorey, Jeffrey S.
结核病仍然是一个全球威胁，部分原因是长期的治疗方案和耐药结核分枝杆菌菌株的流行增加。因此，迫切需要新的药物方案来抗击这种致命的疾病。我们先前合成了一系列新的抗结核化合物，属于咪唑并[1，2-a]吡啶类化合物。这类化合物在体外对结核分枝杆菌表现出较低的NMMIC(最小抑菌浓度)。在这项研究中，咪唑并[1，2-a]吡啶的衍生物(N-(4-(4-chlorophenoxy)benzyl)-2，7-dimethylimidazo[1，2-a]pyridine-3-carboxamide)(ND-09759)被选为有希望的先导化合物，通过小鼠感染模型来确定其保护效果。ND-09759的药代动力学分析表明，给药剂量为30 mg/kg小鼠体重时，最大血药浓度(C-max)为2.9mgg/ml，半衰期为20.1h，给药4周后，每周6天1次给药，小鼠肺、脾结核负担明显减轻，其抗结核活性相当于两种一线抗结核药物异烟肼和利福平。我们观察到，当ND-09759与异烟肼或RMP联合使用时，疗效略高。最后，组织病理学分析显示，与未治疗的小鼠相比，感染ND-09759的小鼠显著减轻了炎症。总而言之，我们的研究结果表明，ND-09759可能是与当前标准抗结核药物联合治疗活动性结核病的有效候选药物。
Tuberculosis remains a global threat due in part to the long treatment regimen and the increased prevalence of drug resistant M. tuberculosis strains. Therefore, new drug regimens are urgently required to combat this deadly disease. We previously synthesized and evaluated a series of new anti-tuberculosis compounds which belong to the family of imidazo[1,2-a]pyridines. This family of compounds showed low nM MIC (minimal inhibitory concentration) values against M. tuberculosis in vitro. In this study, a derivative of imidazo[1,2-a]pyridines, (N-(4-(4-chlorophenoxy)benzyl)-2,7-dimethylimidazo[1,2-a]pyridine-3-carboxamide) (ND-09759), was selected as a promising lead compound to determine its protective efficacy using a mouse infection model. Pharmacokinetic analysis of ND-09759 determined that at a dosage of 30 mg/kg mouse body weight (PO) gave a maximum serum drug concentration (C-max) of 2.9 mu g/ml and a half-life of 20.1 h. M. tuberculosis burden in the lungs and spleens was significantly decreased in mice treated once daily 6 days per week for 4-weeks with ND-09759 compared to untreated mice and this antibiotic activity was equivalent to isoniazid (INH) and rifampicin (RMP), two first-line anti-TB drugs. We observed slightly higher efficacy when using a combination of ND-09759 with either INH or RMP. Finally, the histopathological analysis revealed that infected mice treated with ND-09759 had significantly reduced inflammation relative to untreated mice. In conclusion, our findings indicate ND-09759 might be a potent candidate for the treatment of active TB in combination with current standard anti-TB drugs.