基于吩噻嗪类化合物的新型抗结核小分子化合物的设计、合成及活性研究

Design, synthesis and bioactivity of novel antituberculotic agents based on phenothiazines

目的借助计算机虚拟筛选技术设计并合成新型抗结核小分子化合物。方法以氯丙嗪为模板分子,利用Discoverystudio3.0构建相应的3D药效团模型,并对虚拟化合物库进行筛选;对筛选结果进行手动择优选择,化学合成目标化合物并进行体外抗结核分枝杆菌的活性评价。结果筛选得到活性化合物15个,并合成其中13个,其中化合物9(多巴胺)在体外对结核分枝杆菌表现出中等强度的抑制作用,MIC为8.0μg/ml。结论通过药效团的方法筛选得到了结构较吩噻嗪类化合物简单的抗结核活性小分子多巴胺,该化合物作为抗结核分枝杆菌的先导化合物,较吩噻嗪类具有更大的结构修饰空间。

Objective To design and synthesize novel antituberculotic agents by employing computer aided drug design. Methods Cholorpromazine was used as modulate compound to generate 3D pharmacophore hypotheses in Discovery studio 3.0, and our in-house compounds library was screened. The candidate compounds were cherry-picked manually for synthesis and evaluation for their anti-TB activity in vitro （MTB H37Rv ATCC 27294）. Results 15 active compounds were obtained from the screening and 13 of them were synthesized. The bioassay results showed that compound 9 （dopamine） presented moderately potent inhibitory activity against Mycobacterium tuberculosis in vitro with MIC value of 8.0 μg/ml. Conclusion Dopamine was active against Mycobacterium tuberculosis in vitro with lower molecular weight and LogP value. As a lead antituberculotic compound, it shows potential for optimization to improve anti-TB activity by comparison with the phenothiazines.