Design and synthesis of mycobacterial pks13 inhibitors: Conformationally rigid tetracyclic molecules.
Design and synthesis of mycobacterial pks13 inhibitors: Conformationally rigid tetracyclic molecules.
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分枝杆菌 pks13 抑制剂的设计与合成：构象刚性四环分子
DOI：
10.1016/j.ejmech.2021.113202
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发表时间：
2021-03-05
影响因子：
6.7
通讯作者：
Yu LF
中科院分区：
文献类型：
--
作者：
Zhang W;Liu LL;Lun S;Wang SS;Xiao S;Gunosewoyo H;Yang F;Tang J;Bishai WR;Yu LF
我们先前报道了一系列香豆素类化合物--一种天然存在的含有δ-内酯的四环骨架--它们有效地靶向结核分枝杆菌（Mtb）中聚酮合酶13（Pks 13）的硫酯酶结构域，从而产生上级抗结核（TB）活性。与相应的“开放型”苯并呋喃-3-羧酸乙酯相比，构象受限的香豆素系列的抗TB效果增强，这可能归因于香豆素苯环与位于Pks 13-TE结合结构域的F1670残基苯环之间的额外的π-π堆积相互作用。为了进一步探测这种结合特征，合成了新的四环类似物，并评估了它们对Mtb菌株H37 Rv的抗TB活性。“开放形式”类似物与四环对应物的初步比较再次表明，后者在抗TB活性方面是上级的。特别是含δ-内酰胺的5 H-苯并呋喃并[3，2-c]喹啉-6-酮化合物，得到了最有希望的结果。化合物65表现出针对Mtb H37 Rv的有效活性，MIC值在0.0313至0.0625 μg/mL之间，对Vero细胞具有高选择性（64-128倍）。热稳定性分析支持四环化合物与Pks 13-TE结构域结合的观点，如通过纳米DSF测量的，与观察到的SAR趋势一致。化合物65还显示出对放线菌的优异选择性，因此不太可能对非病原性细菌产生潜在的耐药性。
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 analogs were synthesized and evaluated for their anti-TB activity against the Mtb strain H37Rv. Initial comparison of the ‘open-form’ analogs 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 H37Rv with MIC value between 0.0313 to 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.
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影响因子：
--
作者：
Gavalda, Sabine;Bardou, Fabienne;Quemard, Annaik
通讯作者：
Quemard, Annaik
影响因子：
14.8
作者：
Wilson R;Kumar P;Parashar V;Vilchèze C;Veyron-Churlet R;Freundlich JS;Barnes SW;Walker JR;Szymonifka MJ;Marchiano E;Shenai S;Colangeli R;Jacobs WR Jr;Neiditch MB;Kremer L;Alland D
通讯作者：
Alland D
影响因子：
2.4
作者：
Abrahams KA;Besra GS
通讯作者：
Besra GS
影响因子：
5.2
作者：
Li, Xiaoxun;Du, Yunfei;Zhao, Kang
通讯作者：
Zhao, Kang
影响因子：
16.6
作者：
Lun, Shichun;Guo, Haidan;Onajole, Oluseye K.;Pieroni, Marco;Gunosewoyo, Hendra;Chen, Gang;Tipparaju, Suresh K.;Ammerman, Nicole C.;Kozikowski, Alan P.;Bishai, William R.
通讯作者：
Bishai, William R.