Identification of Novel Coumestan Derivatives as Polyketide Synthase 13 Inhibitors against Mycobacterium tuberculosis. Part II
Identification of Novel Coumestan Derivatives as Polyketide Synthase 13 Inhibitors against Mycobacterium tuberculosis. Part II
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新型 Coumestan 衍生物作为结核分枝杆菌聚酮合酶 13 抑制剂的鉴定。
DOI：
10.1021/acs.jmedchem.9b00010
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发表时间：
2019-04-11
影响因子：
7.3
通讯作者：
Yu, Li-Fang
中科院分区：
文献类型：
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作者：
Zhang, Wei;Lun, Shichun;Yu, Li-Fang
我们小组最近报道了新的香豆素衍生物作为结核分枝杆菌（Mtb）Pks 13-硫酯酶（TE）结构域抑制剂的鉴定，在产生的香豆素耐药Mtb菌落中观察到突变（D1644 G和N1640 K）。在此，我们报告了进一步的结构-活性关系探索，利用现有的Pks 13-TE X-射线共晶结构，导致发现非常有效的香豆素类似物48和50。这些分子对药物敏感（MIC = 0.0039 μ g/mL）和耐药Mtb菌株（MIC = 0.0078 μ g/mL）都具有优异的抗结核活性。此外，优异的体外活性被转化为体内小鼠血清抑制滴定测定，以100 mg/kg施用的香豆素48显示出比分别以10或100 mg/kg施用的异烟肼或TAM 16高8倍的活性。初步的ADME-毒性数据的香豆素是有前途的，再加上合成的实用性，保证进一步在体内疗效评估的香豆素衍生物。
Our group recently reported the identification of novel coumestan derivatives as Mycobacterium tuberculosis (Mtb) Pks13-thioesterase (TE) domain inhibitors, with mutations observed (D1644G and N1640K) in the generated coumestan-resistant Mtb colonies. Herein, we report a further structure-activity relationships exploration exploiting the available Pks13-TE X-ray co-crystal structure that resulted in the discovery of extremely potent coumestan analogues 48 and 50. These molecules possess excellent anti-tuberculosis activity against both the drug-susceptible (MIC = 0.0039 mu g/mL) and drug-resistant Mtb strains (MIC = 0.0078 mu g/mL). Moreover, the excellent in vitro activity is translated to the in vivo mouse serum inhibitory titration assay, with administration of coumestan 48 at 100 mg/kg showing an 8-fold higher activity than that of isoniazid or TAM16 given at 10 or 100 mg/kg, respectively. Preliminary ADME-Tox data for the coumestans were promising and, coupled with the practicality of synthesis, warrant further in vivo efficacy assessments of the coumestan derivatives.