Department of Ophthalmology and Visual Sciences, Pediatrics (Infectious Diseases), Committees on Genetics, Immunology, and Molecular Medicine, Institute of Genomics and Systems Biology, and The College, The University of Chicago, Chicago, IL 60637, USA.
J Med Chem. 2012 Oct 11;55(19):8375-91. doi: 10.1021/jm3007596. Epub 2012 Sep 26.
Toxoplasma gondii (T. gondii) is an apicomplexan parasite that can cause eye disease, brain disease, and death, especially in congenitally infected and immune-compromised people. Novel medicines effective against both active and latent forms of the parasite are greatly needed. The current study focused on the discovery of such medicines by exploring a family of potential inhibitors whose antiapicomplexan activity has not been previously reported. Initial screening efforts revealed that niclosamide, a drug approved for anthelmintic use, possessed promising activity in vitro against T. gondii. This observation inspired the evaluation of the activity of a series of salicylanilides and derivatives. Several inhibitors with activities in the nanomolar range with no appreciable in vitro toxicity to human cells were identified. An initial structure-activity relationship was explored. Four compounds were selected for evaluation in an in vivo model of infection, and two derivatives with potentially enhanced pharmacological parameters demonstrated the best activity profiles.
刚地弓形虫（Toxoplasma gondii）是一种顶复门寄生虫，可导致眼部疾病、脑部疾病和死亡，尤其是在先天性感染和免疫功能低下的人群中。目前迫切需要能够有效针对寄生虫活动期和潜伏期的新型药物。本研究旨在通过探索一个以前未报道过的潜在抑制剂家族来发现此类药物，以寻找具有抗顶复门寄生虫活性的化合物。初步筛选结果表明，已批准用于驱虫的尼氯硝唑在体外对刚地弓形虫具有良好的活性。这一发现促使我们评估一系列水杨酰苯胺及其衍生物的活性。确定了一系列具有纳摩尔级活性且对人细胞无明显体外毒性的抑制剂。初步探讨了结构-活性关系。选择了四种化合物在感染的体内模型中进行评估，两种具有潜在增强的药理参数的衍生物表现出最佳的活性特征。
