Thiazole, oxadiazole, and carboxamide derivatives of artemisinin are highly selective and potent inhibitors of Toxoplasma gondii.
Thiazole, oxadiazole, and carboxamide derivatives of artemisinin are highly selective and potent inhibitors of Toxoplasma gondii.
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DOI：
10.1021/jm901857d
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发表时间：
2010-05-13
影响因子：
7.3
通讯作者：
Woodard, Lauren E.
中科院分区：
文献类型：
--
作者：
Hencken, Christopher P.;Jones-Brando, Lorraine;Bordon, Claudia;Stohler, Remo;Mott, Bryan T.;Yolken, Robert;Posner, Gary H.;Woodard, Lauren E.
我们制备了 23 种新的脱氢青蒿素 (DART) 三恶烷衍生物（11 种噻唑类、2 种恶二唑类和 10 种甲酰胺类），并筛选了它们在弓形虫裂解循环中的体外活性。十五种 (65%) 衍生物对宿主细胞无细胞毒性 (TD50 ≥ 320 μM)。八种噻唑衍生物和两种甲酰胺衍生物显示出对弓形虫生长的有效抑制作用（IC50 = 0.25-0.42 μM），其效力与蒿甲醚（IC50 = 0.31 μM）相当，并且比目前使用的一线药物甲氧苄啶（IC50 = 46 μM）抑制超过100倍。噻唑类作为一个整体比其他衍生物在抑制细胞外和细胞内寄生虫的生长方面更有效。出乎意料的是，两种噻唑三恶烷（5和6）具有杀寄生虫作用；当寄生虫接触 10 μM 药物 24 小时后，两者都不可逆地抑制寄生虫复制，而标准三恶烷药物青蒿素和蒿甲醚则没有杀寄生虫作用。这里描述的一些新的青蒿素衍生物代表了有效的抗三恶烷弓形虫以及用于阐明 DART 类青蒿素衍生物作用机制的分子探针。
We have prepared 23 new dehydroartemisinin (DART) trioxane derivatives (11 thiazoles, 2 oxadiazoles, and 10 carboxamides) and have screened them for in vitro activity in the Toxoplasma lytic cycle. Fifteen (65%) of the derivatives were non-cytotoxic to host cells (TD50 ≥ 320 μM). Eight thiazole derivatives and two carboxamide derivatives displayed effective inhibition of Toxoplasma growth (IC50 = 0.25-0.42 μM), comparable in potency to artemether (IC50 = 0.31 μM) and >100 times more inhibitory than the currently employed front-line drug trimethoprim (IC50 = 46 μM). The thiazoles as a group were more effective than the other derivatives at inhibiting growth of extracellular as well as intracellular parasites. Unexpectedly, two thiazole trioxanes (5 and 6) were parasiticidal; both inhibited parasite replication irreversibly after parasite exposure to 10 μM of drug for 24 hours, whereas the standard trioxane drugs artemisinin and artemether were not parasiticidal. Some of the new derivatives of artemisinin described here represent effective anti-Toxoplasma trioxanes as well as molecular probes for elucidating the mechanism of action of the DART class of artemisinin derivatives.
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影响因子：
4.9
作者：
Krivogorsky, Bogdana;Grundt, Peter;Jones-Brando, Lorraine
通讯作者：
Jones-Brando, Lorraine
影响因子：
7.3
作者：
Chimenti, Franco;Bizzarri, Bruna;Jones-Brando, Lorraine
通讯作者：
Jones-Brando, Lorraine
影响因子：
5.2
作者：
D'Angelo, John G.;Bordon, Claudia;Jones-Brando, Lorraine
通讯作者：
Jones-Brando, Lorraine
影响因子：
--
作者：
Nagamune, Kisaburo;Beatty, Wandy L.;Sibley, L. David
通讯作者：
Sibley, L. David
影响因子：
1.8
作者：
Gangloff, AR;Litvak, J;Rice, KD
通讯作者：
Rice, KD