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, 21231-1044, United States.
Eur J Med Chem. 2021 Mar 5;213:113202. doi: 10.1016/j.ejmech.2021.113202. Epub 2021 Jan 21.
We previously reported a series of coumestans-a naturally occurring tetracyclic scaffold containing a δ-lactone-that effectively target the thioesterase domain of polyketide synthase 13 (Pks13) in Mycobacterium tuberculosis (Mtb), resulting in superior anti-tuberculosis (TB) activity. Compared to the corresponding 'open-form' ethyl benzofuran-3-carboxylates, the enhanced anti-TB effects seen with the conformationally restricted coumestan series could be attributed to the extra π-π stacking interactions between the benzene ring of coumestans and the phenyl ring of F1670 residue located in the Pks13-TE binding domain. To further probe this binding feature, novel tetracyclic analogues were synthesized and evaluated for their anti-TB activity against the Mtb strain HRv. Initial comparison of the 'open-form' analogueues against the tetracyclic counterparts again showed that the latter is superior in terms of anti-TB activity. In particular, the δ-lactam-containing 5H-benzofuro [3,2-c]quinolin-6-ones gave the most promising results. Compound 65 demonstrated potent activity against Mtb HRv with MIC value between 0.0313 and 0.0625 μg/mL, with high selectivity to Vero cells (64-128 fold). The thermal stability analysis supports the notion that the tetracyclic compounds bind to the Pks13-TE domain as measured by nano DSF, consistent with the observed SAR trends. Compound 65 also showed excellent selectivity against actinobacteria and therefore unlikely to develop potential drug resistance to nonpathogenic bacteria.
我们之前报道了一系列香豆素——一种天然存在的四环骨架，含有δ-内酯——它能有效地靶向结核分枝杆菌（Mtb）聚酮合酶 13（Pks13）的硫酯酶结构域，从而具有更好的抗结核（TB）活性。与相应的“开环”乙基苯并呋喃-3-羧酸酯相比，与构象受限的香豆素系列相比，观察到的增强的抗 TB 效果可以归因于香豆素苯环与位于 Pks13-TE 结合域的 F1670 残基的苯环之间额外的 π-π 堆积相互作用。为了进一步探究这种结合特征，合成了新型四环类似物，并评估了它们对 Mtb 菌株 HRv 的抗结核活性。最初比较“开环”类似物与四环类似物，发现后者在抗结核活性方面更具优势。特别是含有 δ-内酰胺的 5H-苯并呋喃[3,2-c]喹啉-6-酮类化合物表现出最有希望的结果。化合物 65 对 Mtb HRv 具有很强的活性，MIC 值在 0.0313 至 0.0625μg/mL 之间，对 Vero 细胞具有高选择性（64-128 倍）。热稳定性分析支持了这样的观点，即四环化合物与 Pks13-TE 结构域结合，这与观察到的 SAR 趋势一致。化合物 65 对放线菌也表现出很好的选择性，因此不太可能对非致病性细菌产生潜在的耐药性。
