Identification of 2,4-Disubstituted Imidazopyridines as Hemozoin Formation Inhibitors with Fast-Killing Kinetics and In Vivo Efficacy in the Plasmodium falciparum NSG Mouse Model.
Identification of 2,4-Disubstituted Imidazopyridines as Hemozoin Formation Inhibitors with Fast-Killing Kinetics and In Vivo Efficacy in the Plasmodium falciparum NSG Mouse Model.
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DOI：
10.1021/acs.jmedchem.0c01411
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发表时间：
2020-11-12
影响因子：
7.3
通讯作者：
Chibale K
中科院分区：
文献类型：
--
作者：
Horatscheck A;Andrijevic A;Nchinda AT;Le Manach C;Paquet T;Khonde LP;Dam J;Pawar K;Taylor D;Lawrence N;Brunschwig C;Gibhard L;Njoroge M;Reader J;van der Watt M;Wicht K;de Sousa ACC;Okombo J;Maepa K;Egan TJ;Birkholtz LM;Basarab GS;Wittlin S;Fish PV;Street LJ;Duffy J;Chibale K
从针对人恶性疟原虫的高通量表型筛选中鉴定了一系列源自SoftFocus激酶文库的2，4-二取代的咪唑并吡啶。命中化合物显示出中等的无性血液阶段活性。在电极导线优化过程中，标记了几个问题，如对多药耐药K1菌株的交叉耐药性、体外细胞毒性和心脏毒性，并通过结构-活性和结构-性质关系研究加以解决。在小鼠中评估了显示期望的体外活性、细胞毒性选择性窗口和微粒体代谢稳定性的化合物的药代动力学性质。先导化合物37在小鼠中显示出良好的暴露，结合针对疟疾寄生虫的良好体外活性，其转化为恶性疟原虫NOD-scid IL-2 R γnull（NSG）小鼠模型中的体内功效。初步的机制研究表明，抑制疟原虫色素的形成作为一个贡献的作用模式。
A series of 2,4-disubstituted imidazopyridines, originating from a SoftFocus Kinase library, was identified from a high throughput phenotypic screen against the human malaria parasite Plasmodium falciparum. Hit compounds showed moderate asexual blood stage activity. During lead optimization, several issues were flagged such as cross-resistance against the multi-drug resistant K1 strain, in vitro cytotoxicity and cardiotoxicity, and were addressed through structure-activity and structure-property relationship studies. Pharmacokinetic properties were assessed in mouse for compounds showing desirable in vitro activity, selectivity window over cytotoxicity and microsomal metabolic stability. Frontrunner compound 37 showed good exposure in mice combined with good in vitro activity against the malaria parasite which translated into in vivo efficacy in the P. falciparum NOD-scid IL-2Rγnull (NSG) mouse model. Preliminary mechanistic studies suggest inhibition of hemozoin formation as a contributing mode of action.
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影响因子：
3.7
作者：
Lelièvre J;Almela MJ;Lozano S;Miguel C;Franco V;Leroy D;Herreros E
通讯作者：
Herreros E
影响因子：
4.9
作者：
Belen Jimenez-Diaz, Maria;Mulet, Teresa;Angulo-Barturen, Inigo
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Angulo-Barturen, Inigo
影响因子：
7.3
作者：
Le Manach, Claire;Nchinda, Aloysius T.;Chibale, Kelly
通讯作者：
Chibale, Kelly
影响因子：
5.2
作者：
van der Watt, Mariette E.;Reader, Janette;Birkholtz, Lyn-Marie
通讯作者：
Birkholtz, Lyn-Marie
影响因子：
7.3
作者：
Jamieson, Craig;Moir, Elizabeth M.;Wishart, Grant
通讯作者：
Wishart, Grant