海洋来源(+)-sclerotiorin衍生物的半合成、抗结核活性与初步构效关系研究

Semisynthesis,antitubercular activity and preliminary structure-activity relationships of marine-derived(+)-sclerotiorin derivatives

目的结核病仍然是世界范围内一个重要的公共卫生问题,因此迫切需要寻找新型抗结核分子。以海洋天然产物(+)-sclerotiorin为原料半合成一系列衍生物,其中包含18个新化合物,通过考察它们的抗结核等活性,探究其初步构效关系。方法利用Mycobacterium marinum和Mycobacterium tuberculosis菌株对衍生物的生物活性进行测定。结果衍生物4、5、8~10和12的抗海分枝杆菌活性与阳性药相当,最低抑菌浓度(MIC90)在16.1~18.9μmol/L之间。此外,衍生物9、11、12和15也显示出中等的抗结核活性。初步构效关系表明喹啉、异喹啉、联苯和联苯醚等基团有利于提升(+)-sclerotiorin衍生物的抗结核活性。衍生物12在结核杆菌蛋白酪氨酸磷酸酶B抑制试验中显示出最强的活性,分子对接的结果表明,它与蛋白的Phe98残基之间存在苯环与苯环间的π-π相互作用。该研究证实了(+)-sclerotiorin衍生物作为抗结核候选药物的潜力。

Objective Tuberculosis remains a significant public health problem worldwide.Therefore,it is an urgent need to discover novel antitubercular molecules.A series of(+)-sclerotiorin derivatives including 18 new compounds was semisynthesized.Their antitubercular activities were evaluated and preliminary structureactivity relationships(SAR)were also discussed.Methods The bioactivity of derivatives was determined by Mycobacterium marinum(Mma)and Mycobacterium tuberculosis(Mtb).Results Derivatives 4,5,8−10 and 12 had the same anti-Mma level as positive controls with MIC90 values of 16.1−18.9μmol/L.Additionally,9,11,12 and 15 also demonstrated moderate activity against Mtb.Preliminary SAR indicated that quinoline,isoquinoline,biphenyl and diphenyl ether groups were beneficial to the antitubercular activity.Mtb protein tyrosine phosphatase B inhibition assay discovered the most active 12 in this series.Docking studies of 12 showed the arene-arene interactions with Phe98 residue of the protein.The research highlighted the potential role of(+)-sclerotiorin derivatives as antitubercular candidates.