Artemisinin derivatives inhibit Toxoplasma gondii in vitro at multiple steps in the lytic cycle
Artemisinin derivatives inhibit Toxoplasma gondii in vitro at multiple steps in the lytic cycle
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DOI：
10.1093/jac/dkn451
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发表时间：
2009-01-01
影响因子：
5.2
通讯作者：
Jones-Brando, Lorraine
中科院分区：
文献类型：
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作者：
D'Angelo, John G.;Bordon, Claudia;Jones-Brando, Lorraine
为了提高青蒿素作为抗弓形虫药物的有效性，我们合成了新的不饱和碳衍生物，然后测试了它们对弓形虫速殖子溶解周期的三个步骤的体外效力。组成型表达β-半乳糖苷酶的弓形虫速殖子和人成纤维细胞宿主细胞。对7个新化合物中的5个（3a-c、3e和3f）进行了寄生虫生长抑制、细胞毒性、复制抑制和寄生虫侵入宿主细胞的抑制试验。弓形虫生长（IC 50 = 1.0-4.4 μ M）;然而，这些中只有三种被证明相对无细胞毒性（TD 50>= 200 μ M）。这5个新的青蒿素衍生物对速殖子复制、附着和侵入宿主细胞的抑制作用与母体化合物ART一样有效或更好。弓形虫裂解周期ART的合成不饱和碳衍生物具有作为用于预防和治疗人类弓形虫病的治疗剂的潜力。
We sought to improve upon the usefulness of artemisinins as anti-Toxoplasma agents by synthesizing new unsaturated, carba derivatives and then testing them for in vitro efficacy against three steps of the lytic cycle of Toxoplasma gondii tachyzoites.Novel derivatives of ART were synthesized and then tested for in vitro antiparasitic activity using T. gondii tachyzoites constitutively expressing beta-galactosidase and human fibroblast host cells. Compounds were evaluated for parasite growth inhibition and cytotoxicity, inhibition of replication and inhibition of parasite invasion of host cells.Five of the seven new derivatives, 3a-c, 3e and 3f, effectively inhibited T. gondii growth (IC50 = 1.0-4.4 mu M); however, only three of these proved to be relatively non-cytotoxic (TD50 >= 200 mu M). The same five derivatives also inhibited tachyzoite replication, and attachment to and invasion of host cells as effectively as or better than the parent compound ART. In addition, one of the derivatives incapable of inhibiting growth, deoxy-3a, was found to inhibit parasite invasion.These new artemisinin derivatives have the ability to inhibit multiple steps of T. gondii's lytic cycle. Synthetic unsaturated, carba derivatives of ART have potential as therapeutic agents for the prevention and treatment of toxoplasmosis in humans.