Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China.
Center for Tuberculosis Research, Department of Medicine, Division of Infectious Disease, Johns Hopkins School of Medicine, Baltimore, MD 21231, USA.
Molecules. 2022 Apr 29;27(9):2844. doi: 10.3390/molecules27092844.
Polyketide synthase 13 (Pks13), an essential enzyme for the survival of (), is an attractive target for new anti-TB agents. In our previous work, we have identified 2-phenylindole derivatives against . The crystallography studies demonstrated that the two-position phenol was solvent-exposed in the Pks13-TE crystal structure and a crucial hydrogen bond was lost while introducing bulkier hydrophobic groups at indole moieties. Thirty-six -phenylindole derivatives were synthesized and evaluated for antitubercular activity using a structure-guided approach. The structure-activity relationship (SAR) studies resulted in the discovery of the potent Compounds and against H37Rv, with an MIC value of 0.0625 μg/mL and 0.125 μg/mL, respectively. The thermal stability analysis showed that they bind with high affinity to the Pks13-TE domain. Preliminary ADME evaluation showed that Compound displayed modest human microsomal stability. This report further validates that targeting Pks13 is a valid strategy for the inhibition of and provides a novel scaffold for developing leading anti-TB compounds.
聚酮合酶 13（Pks13）是生存所必需的酶（），是新型抗结核药物的一个有吸引力的靶点。在我们之前的工作中，我们已经确定了针对的 2-苯基吲哚衍生物。晶体学研究表明，在 Pks13-TE 晶体结构中，两个位置的酚基暴露在溶剂中，而在吲哚部分引入更大的疏水性基团时，会失去关键的氢键。我们合成了 36 个 -苯基吲哚衍生物，并通过结构导向方法评估了它们的抗结核活性。结构-活性关系（SAR）研究发现了针对 H37Rv 的有效化合物和，其 MIC 值分别为 0.0625μg/mL 和 0.125μg/mL。热稳定性分析表明，它们与 Pks13-TE 结构域具有高亲和力结合。初步的 ADME 评估表明，化合物显示出适度的人微粒体稳定性。本报告进一步证实，针对 Pks13 是抑制的有效策略，并为开发领先的抗结核化合物提供了新的支架。
