Lead optimization of aryl and aralkyl amine-based triazolopyrimidine inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase with antimalarial activity in mice.
Lead optimization of aryl and aralkyl amine-based triazolopyrimidine inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase with antimalarial activity in mice.
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DOI：
10.1021/jm200265b
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发表时间：
2011-06-09
影响因子：
7.3
通讯作者：
Rathod PK
中科院分区：
文献类型：
--
作者：
Gujjar R;El Mazouni F;White KL;White J;Creason S;Shackleford DM;Deng X;Charman WN;Bathurst I;Burrows J;Floyd DM;Matthews D;Buckner FS;Charman SA;Phillips MA;Rathod PK
疟疾是世界范围内严重传染病的主要原因之一，但我们维持有效治疗以对抗疾病的能力不断受到耐药性出现的挑战。我们先前报道了一类新的基于三唑并嘧啶的恶性疟原虫二氢乳清酸脱氢酶（PfDHODH）抑制剂的鉴定，其具有抗疟活性，从而发现了新的先导系列和药物开发的新靶点。该系列的活性化合物含有一个三唑并嘧啶环，该环通过一个桥接氮原子与一个芳基相连。在本文中，我们描述了优化芳香族官能度的系统努力，其目标是改善该系列化合物的效力和体内性质。这些研究导致鉴定了两种新的取代的苯胺部分（4-SF 5-Ph和3，5-二-F-4-CF 3-Ph），其在与三唑并嘧啶环偶联时在伯氏疟原虫小鼠疾病模型中显示出良好的血浆暴露和比先前报道的来自该系列的化合物更好的功效。
Malaria is one of the leading causes of severe infectious disease worldwide, yet our ability to maintain effective therapy to combat the illness is continually challenged by the emergence of drug resistance. We previously reported identification of a new class of triazolopyrimidine based P. falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors with antimalarial activity, leading to the discovery of a new lead series and novel target for drug development. Active compounds from the series contained a triazolopyrimidine ring attached to an aromatic group through a bridging nitrogen atom. Herein we describe systematic efforts to optimize the aromatic functionality with the goal of improving potency and in vivo properties of compounds from the series. These studies led to the identification of two new substituted aniline moieties (4-SF5-Ph and 3,5-Di-F-4-CF3-Ph) which, when coupled to the triazolopyrimidine ring showed good plasma exposure and better efficacy in the P. berghei mouse model of the disease, than previously reported compounds from the series.
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影响因子：
1.5
作者：
Ganesan, Suresh M.;Morrisey, Joanne M.;Ke, Hangjun;Painter, Heather J.;Laroiya, Kamal;Phillips, Margaret A.;Rathod, Pradipsinh K.;Mather, Michael W.;Vaidya, Akhil B.
通讯作者：
Vaidya, Akhil B.
影响因子：
4.8
作者：
Baldwin, J;Farajallah, AM;Phillips, MA
通讯作者：
Phillips, MA
影响因子：
4.9
作者：
Nzila, Alexis;Rottmann, Matthias;Diagana, Thierry T.
通讯作者：
Diagana, Thierry T.
影响因子：
4.8
作者：
Patel, Vishal;Booker, Michael;Clardy, Jon
通讯作者：
Clardy, Jon
影响因子：
168.9
作者：
Feachem, Richard G. A.;Phillips, Allison A.;Hwang, Jimee;Cotter, Chris;Wielgosz, Benjamin;Greenwood, Brian M.;Sabot, Oliver;Henry Rodriguez, Mario;Abeyasinghe, Rabindra R.;Ghebreyesus, Tedros Adhanom;Snow, Robert W.
通讯作者：
Snow, Robert W.