抗结核FadD32抑制剂香豆素核心的杂环替代物的发现。
Discovery of heterocyclic replacements for the coumarin core of anti-tubercular FadD32 inhibitors.
作者信息
Fang Chao, Lee Katie K, Nietupski Raymond, Bates Robert H, Fernandez-Menendez Raquel, Lopez-Roman Eva Maria, Guijarro-Lopez Laura, Yin Yunxing, Peng Zuozhong, Gomez James E, Fisher Stewart, Barros-Aguirre David, Hubbard Brian K, Serrano-Wu Michael H, Hung Deborah T
机构信息
The Broad Institute of MIT and Harvard, 415 Main St, Cambridge, MA 02142, USA.
The Broad Institute of MIT and Harvard, 415 Main St, Cambridge, MA 02142, USA; Department of Molecular Biology and Center for Integrative and Computational Biology, Massachusetts General Hospital, 185 Cambridge St, Boston, MA 02114, USA.
出版信息
Bioorg Med Chem Lett. 2018 Dec 1;28(22):3529-3533. doi: 10.1016/j.bmcl.2018.09.037. Epub 2018 Sep 29.
Abstract
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.
摘要
先前的研究确定香豆素支架是抑制结核分枝杆菌（Mtb）FadD32酶活性的起点。在对香豆素抑制剂4进行进一步分析后发现其化学稳定性较差，我们发现喹啉环可避免这种不稳定性，并且具有提供额外取代载体以进一步优化的优势。随后的构效关系（SAR）研究产生了具有强效抗结核活性的喹啉-2-甲酰胺。对吸收、分布、代谢和排泄/药代动力学（ADME/PK）特性的进一步优化最终得到了21b，其在Mtb感染小鼠模型中表现出令人信服的体内疗效。
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1
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J Med Chem. 2018 Feb 8;61(3):791-803. doi: 10.1021/acs.jmedchem.7b01319. Epub 2018 Jan 29.
2
Structure of the Essential FadD32 Enzyme: A Promising Drug Target for Treating Tuberculosis.必需的FadD32酶的结构：一种有前景的治疗结核病的药物靶点。
ACS Infect Dis. 2016 Aug 12;2(8):579-591. doi: 10.1021/acsinfecdis.6b00082. Epub 2016 Jul 1.
3
Insight into Structure-Function Relationships and Inhibition of the Fatty Acyl-AMP Ligase (FadD32) Orthologs from Mycobacteria.深入了解分枝杆菌中脂肪酰基-AMP连接酶（FadD32）直系同源物的结构-功能关系及抑制作用。
J Biol Chem. 2016 Apr 8;291(15):7973-89. doi: 10.1074/jbc.M115.712612. Epub 2016 Feb 21.
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5
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6
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9
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