In vitro selection and in vivo efficacy of piperazine- and alkanediamide-linked bisbenzamidines against Pneumocystis pneumonia in mice
In vitro selection and in vivo efficacy of piperazine- and alkanediamide-linked bisbenzamidines against Pneumocystis pneumonia in mice
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DOI：
10.1128/aac.00126-06
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发表时间：
2006-07-01
影响因子：
4.9
通讯作者：
Huang, Tien L.
中科院分区：
文献类型：
--
作者：
Cushion, Melanie T.;Walzer, Peter D.;Huang, Tien L.
双苯甲脒，如羟乙基磺酸戊烷脒，是芳香族双阳离子化合物，其对肺孢子虫和其他微生物有活性，但通常对宿主有毒。为了确定潜在的抗肺孢子虫药物，我们合成了bisbenzamidine衍生物，其中母体化合物pentamidine通过1，4-哌嗪二基，烷二酰胺或1，3-苯二酰胺部分作为中心连接体进行修饰。在细胞毒性测定中，几种化合物对卡氏肺孢子虫的活性更高，毒性低于喷他脒。在这项研究中，我们评估了九个bisbenzamidine衍生物代表了一系列的体外活性，从高活性到非活性，用于治疗肺孢子虫病的免疫抑制小鼠模型。这些体外活性化合物中的六种，01、02、04、06、100和101，在10 mg/kg体重的剂量下表现出显著的抗感染效力，并且四种化合物，01、04、100和101，与未治疗的感染对照小鼠相比，显示出存活率的显著增加。化合物100在20 mg/kg和40 mg/kg下对感染高度有效，负荷减少> 1，000倍，并且导致与经戊烷脒处理的小鼠（相同剂量）相比改善的存活曲线。所有六种表现出高体外活性的双苯甲脒化合物均显著降低了体内感染;两种具有显著至中等体外活性的化合物12和102在体内具有轻微或无活性，而化合物31在体外无活性并且在体内也无活性。因此，从体外细胞毒性测定中选择高活性化合物可预测肺孢子虫肺炎小鼠模型中的活性。我们的结论是，一些这些bisbenzamidine化合物，特别是化合物100，可能显示出作为新的抗肺孢子虫药物的前景。
Bisbenzamidines, such as pentamidine isethionate, are aromatic dicationic compounds that are active against Pneumocystis and other microbes but are oftentimes toxic to the host. To identify potential anti-Pneumocystis agents, we synthesized bisbenzamidine derivatives in which the parent compound pentamidine was modified by a 1,4-piperazinediyl, alkanediamide, or 1,3-phenylenediamide moiety as the central linker. Several of the compounds were more active against P. carinii and less toxic than pentamidine in cytotoxicity assays. For this study, we evaluated nine bisbenzamidine derivatives representing a range of in vitro activities, from highly active to inactive, for the treatment of pneumocystosis in an immunosuppressed mouse model. Six of these in vitro-active compounds, 01, 02, 04, 06, 100, and 101, exhibited marked efficacies against infection at a dose of 10 mg/kg of body weight, and four compounds, 01, 04, 100, and 101, showed significant increases in survival versus that of untreated infected control mice. Compound 100 was highly efficacious against the infection at 20 mg/kg and 40 mg/kg, with > 1,000-fold reductions in burden, and resulted in improved survival curves versus those for pentamidine-treated mice (at the same doses). All six bisbenzamidine compounds that exhibited high in vitro activity significantly decreased the infection in vivo; two compounds, 12 and 102, with marked to moderate in vitro activities had slight or no activity in vivo, while compound 31 was inactive in vitro and was also inactive in vivo. Thus, the selection of highly active compounds from in vitro cytotoxicity assays was predictive of activity in the mouse model of Pneumocystis pneumonia. We conclude that a number of these bisbenzamidine compounds, especially compound 100, may show promise as new anti-Pneumocystis drugs.