Optimization of Antischistosomal Chemotypes

血吸虫病是一种由血吸虫属吸虫感染引起的热带寄生虫病， 影响全球多达2亿人，其中7.79亿人生活在感染风险中。一种治疗癌症的新药 血吸虫病是迫切需要的，因为吡喹酮是目前最后的药物，而开发 不能忽视耐药性，特别是考虑到它在许多地方病中的大规模使用。我们的长期目标是 发现一种新的口服单剂抗血吸虫药物，对所有寄生虫阶段和 有一种新的作用机制。这项建议目的是确定一种或多种抗血吸虫药物 药物开发候选人。为了实现这一目标，我们将优化四种有希望的抗血吸虫药物 化学类型。我们还将继续研究宿主介导的抗血吸虫作用模式。 芳基海因候选药物AR102。我们提出了四个具体的目标：1)目标的合成和表征 化合物；2)评价目标化合物的药代动力学性质和抗血吸虫活性；3) 使用更严格的分析方法进一步分析选定的目标化合物；以及4)研究作用模式 候选药物AR102。综合体设计将由现有的SAR提供信息，并将最大化结构 硅物理化学剖面图中以前瞻性为导向的多样性基于来自以下项目的迭代反馈 物理化学图谱，体外ADME和细胞毒性(SA 1)，体外和体内抗血吸虫活性 而在体内ADME(SA 2和3)，新的结构假说将出现，我们将合成额外的靶点 化合物。目标化合物将使用明确定义的级数通过各种分析 标准。我们认为这项拟议的研究具有创新性，原因如下：第一，芳基海因和 臭氧化合物已经证明了体内抗血吸虫的效果，但体外(体外)活性很低，相反 通常情况下，先导化合物在体外有活性，但在体内没有活性。第二，氮杂酮 内酰胺类化学型和备用三环咪唑烷-4-酮系列化合物是相对罕见的例子 中环化合物(8至11个原子)。第三，我们试图界定独特的宿主介导的模式 抗血吸虫候选药物AR102的作用。这项工作的预期结果是确定一个或 更多的抗血吸虫药物开发候选药物对所有寄生虫阶段有效。用于抗血吸虫药物 候选药物AR102，我们将定义其宿主介导的抗血吸虫作用模式。这项建议 研究意义重大，因为一种新药将在耐药患者的化疗中发挥重要作用 在控制这种寄生虫病的综合控制方案中，可能具有重要的价值。

Schistosomiasis is a tropical parasitic disease caused by infections with flukes of the genus Schistosoma, affecting as many as 200 million individuals worldwide, with 779 million living at risk of infection. A new drug for schistosomiasis is urgently needed as praziquantel is currently the drug of last resort and the development of resistance cannot be ignored, particularly in view of its large-­scale use in many endemic. Our long-­term goal is to discover a new orally active single-­dose antischistosomal drug with activities against all parasite stages and with a novel mechanism of action. The objective of this proposal is to identify one or more antischistosomal drug development candidates. To accomplish this objective, we will optimize four promising antischistosomal chemotypes. We will also continue our investigation into the host-­mediated antischistosomal mode of action of aryl hydantoin drug candidate AR102. We propose four specific aims: 1) to synthesize and characterize target compounds; 2) to assess pharmacokinetic properties and antischistosomal activity of target compounds; 3) to further profile selected target compounds using more rigorous assays; and 4) to investigate the mode of action of drug candidate AR102. Compound design will be informed by existing SAR and will maximize structural diversity guided by prospective in silico physicochemical profiling. Based on iterative feedback from physicochemical profiling, in vitro ADME, and cytotoxicity (SA 1), ex vivo and in vivo antischistosomal activity and in vivo ADME (SA 2 and 3), new structural hypotheses will arise, and we will synthesize additional target compounds. Target compounds will progress through the various assays using clearly defined progression criteria. We suggest that this proposed research is innovative for several reasons First, the aryl hydantoins and ozonides have proven in vivo antischistosomal efficacy, but have very low ex vivo (in vitro) activity, the reverse of the usual situation where lead compounds have in vitro but no in vivo activity. Second, the azonine keto lactam chemotype and backup tricyclic imidazolidin-­4-­one compound series are examples of relatively rare medium-­ring compounds (8 to 11 atoms). Third, we seek to demarcate the unique host-­mediated mode of action of antischistosomal drug candidate AR102. The expected outcome from this work is to identify one or more antischistosomal drug development candidates effective against all parasite stages. For antischistosomal drug candidate AR102, we will define its host-­mediated antischistosomal mode of action. This proposed research is significant because a new drug would be important in the chemotherapy of drug-­resistant schistosomiasis and likely be valuable in integrated control programs to curb this parasitic disease.