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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Design and synthesis of mycobacterial pks13 inhibitors: Conformationally rigid tetracyclic molecules
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Design and synthesis of mycobacterial pks13 inhibitors: Conformationally rigid tetracyclic molecules

机译：分枝杆菌PKS13抑制剂的设计与合成：构型刚性四环分子

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摘要

We previously reported a series of coumestans-a naturally occurring tetracyclic scaffold containing a delta-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 pi-pi 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 H37Rv. 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 delta-lactam-containing 5H-benzofuro [3,2-c]quinolin-6-ones gave the most promising results. Compound 65 demonstrated potent activity against Mtb H(37)Rv with MIC value between 0.0313 and 0.0625 mu g/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. (C) 2021 Elsevier Masson SAS. All rights reserved.
机译：我们之前报道了一系列香豆素——一种含有δ内酯的天然四环支架，有效地靶向结核分枝杆菌（Mtb）中聚酮合酶13（Pks13）的硫酯酶结构域，从而产生优异的抗结核（TB）活性。与相应的“开放式”乙基苯并呋喃-3-羧酸盐相比，构象受限的香豆素系列所表现出的增强抗结核作用可归因于香豆素的苯环和位于Pks13 TE结合域的F1670残基的苯环之间额外的pi堆积相互作用。为了进一步探索这种结合特征，我们合成了新型四环类似物，并评估了它们对结核分枝杆菌H37Rv株的抗结核活性。“开放式”类似物与四环类似物的初步比较再次表明，四环类似物在抗结核活性方面优于四环类似物。特别是，含有5H苯并呋喃[3,2-c]喹啉-6-酮的δ-内酰胺给出了最有希望的结果。化合物65表现出对Mtb H（37）Rv的有效活性，MIC值在0.0313和0.0625μg/mL之间，对Vero细胞具有高选择性（64-128倍）。热稳定性分析支持通过纳米DSF测量的四环化合物与Pks13 TE结构域结合的概念，这与观察到的SAR趋势一致。化合物65对放线菌也表现出良好的选择性，因此不太可能对非致病性细菌产生潜在耐药性。（c）2021爱思唯尔马松SAS。版权所有。

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