新型弓形虫抑制剂化学类型。
Novel Toxoplasma gondii inhibitor chemotypes.
作者信息
Sanford A G, Schulze T T, Potluri L P, Hemsley R M, Larson J J, Judge A K, Zach S J, Wang X, Charman S A, Vennerstrom J L, Davis P H
机构信息
Department of Biology, University of Nebraska at Omaha, Omaha, NE, USA.
College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, USA.
出版信息
Parasitol Int. 2018 Apr;67(2):107-111. doi: 10.1016/j.parint.2017.10.010. Epub 2018 Jan 4.
We profiled three novel T. gondii inhibitors identified from an antimalarial phenotypic high throughput screen (HTS) campaign: styryl 4-oxo-1,3-benzoxazin-4-one KG3, tetrahydrobenzo[b]pyran KG7, and benzoquinone hydrazone KG8. These compounds inhibit T. gondii in vitro with IC values ranging from 0.3 to 2μM, comparable to that of 0.25 to 1.5μM for the control drug pyrimethamine. KG3 had no measurable cytotoxicity against five mammalian cell lines, whereas KG7 and KG8 inhibited the growth of 2 of 5 cell lines with KG8 being the least selective for T. gondii. None of the compounds were mutagenic in an Ames assay. Experimental gLogD and calculated PSA values for the three compounds were well within the ranges predicted to be favorable for good ADME, even though each compound had relatively low aqueous solubility. All three compounds were metabolically unstable, especially KG3 and KG7. Multiple IP doses of 5mg/kg KG7 and KG8 increased survival in a T. gondii mouse model. Despite their liabilities, we suggest that these compounds are useful starting points for chemical prospecting, scaffold-hopping, and optimization.
我们分析了从抗疟表型高通量筛选（HTS）活动中鉴定出的三种新型弓形虫抑制剂：苯乙烯基4-氧代-1,3-苯并恶嗪-4-酮KG3、四氢苯并[b]吡喃KG7和苯醌腙KG8。这些化合物在体外抑制弓形虫，IC值范围为0.3至2μM，与对照药物乙胺嘧啶的0.25至1.5μM相当。KG3对五种哺乳动物细胞系没有可测量的细胞毒性，而KG7和KG8抑制了5种细胞系中的2种细胞系的生长，其中KG8对弓形虫的选择性最低。在艾姆斯试验中，这些化合物均无致突变性。尽管每种化合物的水溶性相对较低，但这三种化合物的实验性gLogD和计算出的PSA值均完全在预测有利于良好吸收、分布、代谢和排泄（ADME）的范围内。所有三种化合物在代谢上都不稳定，尤其是KG3和KG7。多次腹腔注射5mg/kg的KG7和KG8可提高弓形虫小鼠模型的存活率。尽管它们存在不足之处，但我们认为这些化合物是化学勘探、骨架跳跃和优化的有用起点。
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