Spirocycle MmpL3 Inhibitors with Improved hERG and Cytotoxicity Profiles as Inhibitors of Mycobacterium tuberculosis Growth.
Spirocycle MmpL3 Inhibitors with Improved hERG and Cytotoxicity Profiles as Inhibitors of Mycobacterium tuberculosis Growth.
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DOI：
10.1021/acsomega.0c05589
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发表时间：
2021-01-26
期刊：
影响因子：
4.1
通讯作者：
Parish T
中科院分区：
文献类型：
--
作者：
Ray PC;Huggett M;Turner PA;Taylor M;Cleghorn LAT;Early J;Kumar A;Bonnett SA;Flint L;Joerss D;Johnson J;Korkegian A;Mullen S;Moure AL;Davis SH;Murugesan D;Mathieson M;Caldwell N;Engelhart CA;Schnappinger D;Epemolu O;Zuccotto F;Riley J;Scullion P;Stojanovski L;Massoudi L;Robertson GT;Lenaerts AJ;Freiberg G;Kempf DJ;Masquelin T;Hipskind PA;Odingo J;Read KD;Green SR;Wyatt PG;Parish T
随着多药耐药结核分枝杆菌菌株的出现，迫切需要具有新型作用机制的新型口服药物。许多体外抗结核活性强的支架已经从表型筛选中鉴定出来，它们似乎靶向MmpL3。然而，支架通常是亲脂性的，这有助于分解成疏水膜，并且一些支架含有碱性胺基。高度亲脂性碱胺对哺乳动物细胞系具有典型的细胞毒性，并具有相关的脱靶风险，如抑制人醚-à-go-go相关基因（hERG）和IKr钾电流调节。据报道，螺旋环化合物3靶向MmpL3，并在小鼠急性结核（TB）感染模型中显示出良好的疗效。然而，这种高度亲脂性的单碱胺具有细胞毒性并抑制hERG离子通道。本文描述了相关的螺环（1-2），这些螺环是在礼来公司文库抗结核分枝杆菌表型筛选后鉴定出来的。新型n -烷基化吡唑部分具有更好的物理化学性质，优化后鉴定出一个中性离子系列，例如铅29，具有降低HepG2细胞毒性和有限的hERG离子通道抑制作用。携带MmpL3突变的菌株对29株具有耐药性，在复制条件下，29株对结核分枝杆菌表现出杀菌活性。不幸的是，化合物29对结核感染急性模型没有疗效；这很可能是由于体内暴露仅在有限的时间内保持在最低抑制浓度以上。
With the emergence of multi-drug-resistant strains of Mycobacterium tuberculosis, there is a pressing need for new oral drugs with novel mechanisms of action. A number of scaffolds with potent anti-tubercular in vitro activity have been identified from phenotypic screening that appear to target MmpL3. However, the scaffolds are typically lipophilic, which facilitates partitioning into hydrophobic membranes, and several contain basic amine groups. Highly lipophilic basic amines are typically cytotoxic against mammalian cell lines and have associated off-target risks, such as inhibition of human ether-à-go-go related gene (hERG) and IKr potassium current modulation. The spirocycle compound 3 was reported to target MmpL3 and displayed promising efficacy in a murine model of acute tuberculosis (TB) infection. However, this highly lipophilic monobasic amine was cytotoxic and inhibited the hERG ion channel. Herein, the related spirocycles (1–2) are described, which were identified following phenotypic screening of the Eli Lilly corporate library against M. tuberculosis. The novel N-alkylated pyrazole portion offered improved physicochemical properties, and optimization led to identification of a zwitterion series, exemplified by lead 29, with decreased HepG2 cytotoxicity as well as limited hERG ion channel inhibition. Strains with mutations in MmpL3 were resistant to 29, and under replicating conditions, 29 demonstrated bactericidal activity against M. tuberculosis. Unfortunately, compound 29 had no efficacy in an acute model of TB infection; this was most likely due to the in vivo exposure remaining above the minimal inhibitory concentration for only a limited time.
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