Discovery of heterocyclic replacements for the coumarin core of anti-tubercular FadD32 inhibitors

被引：18

作者：

Fang, Chao ^{[1
]}

Lee, Katie K. ^{[1
,2
,3
]}

Nietupski, Raymond ^{[1
]}

Bates, Robert H. ^{[5
]}

Fernandez-Menendez, Raquel ^{[5
]}

Maria Lopez-Roman, Eva ^{[5
]}

Guijarro-Lopez, Laura ^{[5
]}

Yin, Yunxing ^{[6
]}

Peng, Zuozhong ^{[7
]}

Gomez, James E. ^{[1
,2
,3
]}

Fisher, Stewart ^{[1
]}

Barros-Aguirre, David ^{[5
]}

Hubbard, Brian K. ^{[1
]}

Serrano-Wu, Michael H. ^{[1
]}

Hung, Deborah T. ^{[1
,2
,3
,4
]}

机构：

[1] Broad Inst MIT & Harvard, 415 Main St, Cambridge, MA 02142 USA

[2] Massachusetts Gen Hosp, Dept Mol Biol, 185 Cambridge St, Boston, MA 02114 USA

[3] Massachusetts Gen Hosp, Ctr Integrat & Computat Biol, 185 Cambridge St, Boston, MA 02114 USA

[4] Harvard Med Sch, Dept Genet, 77 Ave Louis Pasteur, Boston, MA 02115 USA

[5] GlaxoSmithKline, Dis Developing World, Severn Ochoa 2, Madrid 28760, Spain

[6] WuXi AppTec, Tianjin Econ Technol Dev Area TEDA, 168 Nanhai Rd, Tianjin 300457, Peoples R China

[7] WuXi AppTec, 288 Fute Zhong Rd, Shanghai 200131, Peoples R China

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2018年 / 28卷 / 22期

关键词：

Mycobacterium tuberculosis; FadD32; inhibitor; Structure-activity relationship; Quinoline-2-carboxamide; In vivo efficacy; MYCOBACTERIUM-TUBERCULOSIS; TARGET;

D O I：

10.1016/j.bmcl.2018.09.037

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Previous work established a coumarin scaffold as a starting point for inhibition of Mycobacterium tuberculosis (Mtb) FadD32 enzymatic activity. After further profiling of the coumarin inhibitor 4 revealed chemical instability, we discovered that a quinoline ring circumvented this instability and had the advantage of offering additional substitution vectors to further optimize. Ensuing SAR studies gave rise to quinoline-2-carboxamides with potent anti-tubercular activity. Further optimization of ADME/PK properties culminated in 21b that exhibited compelling in vivo efficacy in a mouse model of Mtb infection.

引用

页码：3529 / 3533

页数：5

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