Bioisosteric transformations and permutations in the triazolopyrimidine scaffold to identify the minimum pharmacophore required for inhibitory activity against Plasmodium falciparum dihydroorotate dehydrogenase.
Bioisosteric transformations and permutations in the triazolopyrimidine scaffold to identify the minimum pharmacophore required for inhibitory activity against Plasmodium falciparum dihydroorotate dehydrogenase.
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三唑吡啶支架中的生物酶转化和置换，以鉴定抑制性恶性疟原虫二氢二酸疟原虫脱氢酶所需的最低药效团。
DOI：
10.1021/jm300351w
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发表时间：
2012-09-13
影响因子：
7.3
通讯作者：
Rathod, Pradipsinh K.
中科院分区：
文献类型：
--
作者：
Marwaha, Alka;White, John;El Mazouni, Farah;Creason, Sharon A.;Kokkonda, Sreekanth;Buckner, Frederick S.;Charman, Susan A.;Phillips, Margaret A.;Rathod, Pradipsinh K.
恶性疟原虫每年造成约100万人死亡。然而，不断增加的耐药性对现有的药物疗法构成了持续的威胁。我们以前报道了一些有效的和选择性的三唑并嘧啶为基础的抑制剂恶性疟原虫二氢乳清酸脱氢酶抑制寄生虫在体外生长具有类似的活性。该系列的先导优化导致最近鉴定出临床前候选物，其在小鼠中显示出对恶性疟原虫的良好活性。作为围绕该支架的备份程序的一部分，我们探索了三唑并嘧啶环中的杂原子重排和取代，并鉴定了作为PfDHODH抑制剂具有活性的几种其他环构型。根据氨基苯胺取代的性质，咪唑并[1，2-α]嘧啶的结合强度略高于三唑并嘧啶。DSM 151是该系列中的最佳候选物，其结合亲和力（PfDHODH IC 50 = 0.077 μM）是等效三唑并嘧啶的4倍，并在伯氏疟原虫模型中抑制体内寄生虫。
Plasmodium falciparum causes approximately 1 million deaths annually. However increasing resistance imposes a continuous threat to existing drug therapies. We previously reported a number of potent and selective triazolopyrimidine-based inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase that inhibit parasite in vitro growth with similar activity. Lead optimization of this series led to the recent identification of a preclinical candidate, showing good activity against P. falciparum in mice. As part of a backup program around this scaffold, we explored heteroatom rearrangement and substitution in the triazolopyrimidine ring and have identified several other ring configurations that are active as PfDHODH inhibitors. The imidazo[1,2-α]pyrimidines were shown to bind somewhat more potently than the triazolopyrimidines depending on the nature of the amino aniline substitution. DSM151, the best candidate in this series, binds with 4-fold better affinity (PfDHODH IC50 = 0.077 μM) than the equivalent triazolopyrimidine and suppresses parasites in vivo in the P. berghei model.
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结构引导的三唑嘧啶环取代基的铅优化鉴定出具有临床候选潜力的有效的恶性疟原虫二氢二酸二氢二酸脱氢酶抑制剂。
影响因子：
7.3
作者：
Coteron, Jose M.;Marco, Maria;Esquivias, Jorge;Deng, Xiaoyi;White, Karen L.;White, John;Koltun, Maria;El Mazouni, Farah;Kokkonda, Sreekanth;Katneni, Kasiram;Bhamidipati, Ravi;Shackleford, David M.;Angulo-Barturen, Inigo;Ferrer, Santiago B.;Belen Jimenez-Diaz, Maria;Gamo, Francisco-Javier;Goldsmith, Elizabeth J.;Charman, William N.;Bathurst, Ian;Floyd, David;Matthews, David;Burrows, Jeremy N.;Rathod, Pradipsinh K.;Charman, Susan A.;Phillips, Margaret A.
通讯作者：
Phillips, Margaret A.
影响因子：
4.8
作者：
Baldwin, J;Farajallah, AM;Phillips, MA
通讯作者：
Phillips, MA
DOI：
10.1016/s0969-2126(00)00077-0
发表时间：
2000-01-15
期刊：
STRUCTURE WITH FOLDING & DESIGN
影响因子：
--
作者：
Liu, SP;Neidhardt, EA;Clardy, J
通讯作者：
Clardy, J
影响因子：
7.3
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
通讯作者：
Rathod PK
影响因子：
15.8
作者：
Guerra, Carlos A.;Gikandi, Priscilla W.;Tatem, Andrew J.;Noor, Abdisalan M.;Smith, Dave L.;Hay, Simon I.;Snow, Robert W.
通讯作者：
Snow, Robert W.