吲哚-2-酮-3-螺噻嗪酮类化合物的抗结核活性研究

Tuberculosis (TB) is an infectious contagious disease caused mainly by Mycobacterium tuberculosis (Mtb) and is one of the most devastating public health problems worldwide. However, the genetic variation leads to the emergence of multidrug resistant (MDR) TB and extensively drug-resistant (XDR) TB, which has alarmed clinicians and threatens the positive gains made in combating TB. Hence, it is imperative to develop new classes of antitubercular agents for this worldwide clinical need that are effective against drug-resistant TB and ideally possess a novel mode of action. Indolin-2-on-3-spirothiazolidinones have been identified as a potent anti-TB lead by high-throughput screening of compound libraries for the first time. We intend to further modify and synthesize the diversified lead compounds using rational drug design, and discover the structure-activity of the compounds. Furthermore, the toxicity, pharmacokinetics, and mode of action will also be studied, which paves the way of development of anti-TB drug with high activity, low toxicity, selectivity, and intellectual property rights.

结核病是由结核分枝杆菌引起的第二高死亡率的感染性疾病，是严重的全球性健康问题。新药及新疗法的研发是控制结核病的核心。本项目通过对化合物库的高通量筛选发现吲哚酮噻嗪酮类螺环衍生物具有很好的抗结核活性。在初步的构效关系研究的基础上，我们拟进一步对该类化合物进行结构修饰，研究该类化合物的作用机制，开展药代动力学、毒理等临床前研究，为研发出具有具有自主知识产权的抗耐药性结核新药奠定基础。

结核病是由结核分枝杆菌引起的能够与艾滋病共感染的致死性疾病，是严重的全球性健康问题。近年来，研究发现耐多药结核菌的出现给全球结核病的防控带来了严重威胁。因此，发展具有新型作用机制的新药显得尤为迫切。该项目在前期研究基础上，我们通过设计合成出了近300个吲哚酮噻嗪酮类螺环衍生物，并进行了活性测试，确定了这类化合物的结构与抗结核活性关系。对其中两个活性较好的化合物进行了初步的药代动力学和毒性实验。结果发现其具有较长的半衰期，没有出现明显的心脏毒性。小鼠模型实验发现部分化合物在肺部或脾内具有较好的抑菌作用。作用机制初步研究表明，这类化合物抑制或杀死处于非复制状态的结核菌，其作用位点可能为结核分枝杆菌的酪氨酸磷酸酶基因MptpB。此外，为进一步开发相关的噻嗪酮类螺环衍生物抗结核活性，我们在现有研究基础上，继续发展高效的杂环合成(如螺吲哚林-3,2-吡咯啉酮、菲啰啉连咔唑以及β-咔啉等衍生物)方法，为今后开展新抗结核药物研究提供保障。