二芳基喹啉类化合物抗结核效果及安全性

Anti-tuberculosis effect and safety of diarylquinoline compounds

摘要:

【背景】贝达喹啉作为治疗结核病的一种特效药，二芳基喹啉是以喹啉为骨架合成的一类化合物，但对于其在抗结核方面的研究鲜有报道。【目的】探究二芳基喹啉类化合物H2对结核分枝杆菌的抑菌效果和药物安全性，为药物研发奠定基础。【方法】采用比例法测定H2对不同结核分枝杆菌的最低抑菌浓度(minimum inhibitory concentration，MIC)和最小杀菌浓度(minimum bactericidal concentration，MBC)，并选一线抗结核药物(异烟肼、利福平、乙胺丁醇)作为阳性对照，4周后观察结果；选昆明小鼠40只，分5个剂量组，灌胃给药，观察小鼠不同剂量下的存活状态及外观体征变化；根据LD50剂量，采用7 d喂养实验，设3个剂量组(高、中、低)和空白对照组。实验结束，采取外周血并剖检，取各脏器称重，制作切片，观察病理改变。【结果】体外抑菌实验显示，H2对H37Rv的MIC与INH较相似，对耐药菌株仍有较好的抑菌效果；体内毒性试验显示，小鼠LD50为582.77 mg/kg。与空白组相比，高剂量组体质量在第5天差异极显著(P<0.01)，第6、7天差异显著(P<0.05)，红细胞计数、血小板和血小板比客差异显著(P<0.05)，肝脏系数差异极显著(P<0.01)。镜下所见，剂量组肾脏组织有轻度炎症和水肿，肾小管上皮有轻度的水泡样变性，肝脏存在轻度的水肿和肝细胞的坏死。【结论】该化合物对不同结核分枝杆菌有较好的抑菌效果，有进一步开发、优化的意义。

Abstract:

[Background] Bedaquiline is the special medicine for the treatment of tuberculosis. The diarylquinolines were kinds of compounds which were synthesized by the quinoline skeleton, and were rarely reported about its research on the anti-tuberculosis. [Objective] The bacteriostatic effect on Mycobacterium tuberculosis and drug safety of diarylquinoline compounds (H2) were studied, laying the foundation for drug research and development. [Methods] First, the minimum inhibitory concentration (MIC) and minnium bactericidal concentration (MBC) of H2 against different Mycobacterium tuberculosis were determined by proportional method, and the first-line anti-tuberculosis drugs (isoniazid, rifampicin, ethambutol) were selected as positive control. The results were observed four weeks later. 40 kunming mice were divided into 5 dose groups. The survival status and appearance signs of Kunming mice at different doses were observed by gavage. According to the dose of LD50, three dose groups (high, mid, low) and blank control group were fed with 7 days. At the end of the experiment, the peripheral blood was examined, the organs were weighed, the tissue sections were made, and the pathological changes were observed. [Results] In vitro bacteriostatic test showed that the MIC of H2 to H37Rv is similar to INH, and it still has a good bacteriostatic effect on drug-resistant strains. In vivo toxicity test showed that the LD50 of mice was 582.77 mg/kg. Compared with the control group, in the high dose group, the body mass was very significantly different at the 5th day (P<0.01), and at the 6th and 7th day were significantly different (P<0.05), and the red blood cell, platelet, plateletocrit (P<0.05), and the liver coefficient (P<0.01). Microscopic results showed that there were mild inflammation and edema in renal tissue, and mild vesicular degeneration in renal tubular epithelial tissue, and mild edema in liver and necrosis of hepatocytes in the dose group. [Conclusion] The compound has good bacteriostatic effect on different Mycobacterium tuberculosis, bringing significance of further development and optimization.