College of Science and Engineering, Flinders University, Bedford Park, SA 5042, Australia.
State Key Laboratory of Respiratory Disease, Guangdong-Hong Kong-Macao Joint Laboratory of Respiratory Infectious Diseases, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
Eur J Med Chem. 2023 Nov 5;259:115637. doi: 10.1016/j.ejmech.2023.115637. Epub 2023 Jul 19.
A series of 3-methoxy-2-phenylimidazo[1,2-b]pyridazine derivatives which were highly active against autoluminescent Mycobacterium tuberculosis (Mtb) and Mycobacterium marinum (Mm) in an in vitro assay were identified. SAR analysis showed that the most active compounds, which included a phenyl group bearing fluoro substituent(s) at C2, a methoxy function at C3, and a benzyl-heteroatom moiety at C6, exhibited in vitro MIC values generally around 0.63-1.26 μM against Mtb and Mm. However, these compounds were inactive against Mtb in vivo (mice), and investigations revealed very short metabolic half-lives (<10 min) when incubated with mouse liver microsomes. Multiple observations of side products produced from oxidative cleavage of the imidazole moiety during the chemical synthesis work suggested that this is a likely metabolic pathway leading to the lack of observed activity in vivo.
一系列 3-甲氧基-2-苯基咪唑并[1,2-b]哒嗪衍生物在体外试验中对发光分枝杆菌（Mtb）和海分枝杆菌（Mm）具有高度的活性。SAR 分析表明，最活跃的化合物包括在 C2 位带有氟取代基的苯基、C3 位的甲氧基和 C6 位的苄基杂原子部分，对 Mtb 和 Mm 的体外 MIC 值通常在 0.63-1.26 μM 左右。然而，这些化合物在体内（小鼠）对 Mtb 没有活性，并且在与小鼠肝微粒体孵育时发现非常短的代谢半衰期（<10 分钟）。在化学合成工作中对咪唑部分氧化裂解产生的副产物的多次观察表明，这可能是导致体内观察到缺乏活性的代谢途径。
