Derivatives of Natural Product Agrimophol as Disruptors of Intrabacterial pH Homeostasis in Mycobacterium tuberculosis
Derivatives of Natural Product Agrimophol as Disruptors of Intrabacterial pH Homeostasis in Mycobacterium tuberculosis
复制标题
天然产物阿格里莫酚衍生物作为结核分枝杆菌菌内 pH 稳态的破坏者
DOI：
10.1021/acsinfecdis.8b00325
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发表时间：
2019-07-01
影响因子：
5.3
通讯作者：
Liu, Gang
中科院分区：
文献类型：
--
作者：
Wu, Jie;Mu, Ran;Liu, Gang
本文报道了一种新的结核分枝杆菌（Mtb）细菌内pH（pH（IB））稳态破坏剂--鹤草酚（1）的合理药物化学。通过对化合物1构效关系、二苯甲烷骨架的骨架跳跃、药效团置换策略以及构效关系的研究，得到了一个新的化合物5a。与1相比，化合物5a在将pH（IB）降低至pH 6.0的能力方面显示出100倍增加的效力，并且类似地改善了针对牛分枝杆菌-BCG和Mtb两者的杀分枝杆菌活性。化合物5a在人肝微粒体和肝细胞中具有改善的代谢稳定性、较低的细胞毒性、较高的选择性指数和与天然1相似的pK（a）值。这项研究为旧药物引入了一种新的支架，通过降低pH值（IB）提高了杀分枝杆菌活性，并可能有助于寻找新的药物来克服结核病治疗中的耐药性和持久性。
This article reports the rational medicinal chemistry of a natural product, agrimophol (1), as a new disruptor of intrabacterial pH (pH(IB)) homeostasis in Mycobacterium tuberculosis (Mtb). Through the systematic investigation of the structure-activity relationship of 1, scaffold-hopping of the diphenylmethane scaffold, pharmacophore displacement strategies, and studies of the structure-metabolism relationship, a new derivative 5a was achieved. Compound 5a showed 100-fold increased potency in the ability to reduce pH(IB) to pH 6.0 and similarly improved mycobactericidal activity compared with 1 against both Mycobacterium bovis-BCG and Mtb. Compound 5a possessed improved metabolic stability in human liver microsomes and hepatocytes, lower cytotoxicity, higher selectivity index, and similar pK(a) value to natural 1. This study introduces a novel scaffold to an old drug, resulting in improved mycobactericidal activity through decreasing pH(IB), and may contribute to the critical search for new agents to overcome drug resistance and persistence in the treatment of tuberculosis.