Development of thiophen-2-yl-phenylpyrimidines for treatment of schistosomiasis

摘要 血吸虫病是一种贫困疾病，感染了全世界2亿多人， 百万风险目前对该病的治疗和控制仅依赖于一种药物，吡喹酮（PZQ）- a 一旦出现抗药性，情况就很不稳定。此外，PZQ的治疗概况并不理想。的 因此，世界卫生组织宣布血吸虫病是一种急需新疗法的疾病。 needed.微管是真核细胞骨架的重要组成部分。MT靶向 药物，包括MT稳定和去稳定化合物，形成癌症化疗的基石; 此外，研究表明，这些化合物可用于治疗寄生虫感染，包括 血吸虫病因此，我们在表型上筛选了>300种MT稳定剂的文库， 具有良好的药物样性质，具有抗溶酶体活性。我们确定了不同的成员 苯基嘧啶（PP）类，表现出显著的生物活性。结构活性的进一步探讨 最有前途的化合物的SAR关系（SAR）确定了一系列新的噻吩-2-基- 苯基嘧啶（TPP）衍生物，其产生曼氏血吸虫的有效且持久的麻痹， 在哺乳动物细胞中不引起MT变化或细胞毒性的化合物浓度。鉴于这些在 体外结果表明，这些TPP有望成为候选抗溶酶体药物。 评估和开发这些化合物作为治疗药物的下一个关键步骤是： 在血吸虫病中，目的是证明一种或多种TPP候选物的耐受性和体内功效。朝向 为此，我们提出两个目标： (1)通过其设计完成30-50个TPP的结构活性/性质关系（SAR/SPR）研究， 合成和体外表型评价与S. mansoni将进行药代动力学（PK）随访 分析满足体外抗肿瘤的所有预定选择标准的最有希望的化合物（3-6）， 溶酶体活性、选择性和“药物样”理化性质。 (2)在重新合成性能最好的1-3种化合物后，确定其体内最大耐受剂量 并随后确定它们在S.曼氏感染。 拟议的项目将提供证据，证明体外和体内抗人β-内酰胺酶之间的相关性。 活动，并确定一个或多个铅结构，用于未来的研究，将专门关注铅 优化和对作用机制的理解。

ABSTRACT Schistosomiasis is a disease of poverty that infects over 200 million people worldwide and places another 700 million at risk. Current treatment and control of the disease rely on just one drug, praziquantel (PZQ) - a precarious situation should drug resistance emerge. Furthermore, the therapeutic profile of PZQ is not ideal. The World Health Organization has therefore declared schistosomiasis a disease for which new therapies are urgently needed. Microtubules (MTs) are essential components of the cytoskeleton in all eukaryotic cells. MT-targeting drugs, which include MT-stabilizing and -destabilizing compounds, form a cornerstone of cancer chemotherapy; in addition, studies suggest that such compounds may be useful to treat parasitic infections, including schistosomiasis. Accordingly, we phenotypically screened a library of >300 MT-stabilizing agents with generally favorable drug-like properties for anti-schistosomal activity. We identified different members of the phenylpyrimidine (PP) class that exhibited marked bioactivity. Further exploration of the structure activity relationships (SARs) of the most promising compounds identified a series of novel thiophen-2-yl- phenylpyrimidine (TPP) derivatives that produce a potent and long-lasting paralysis of Schistosoma mansoni at compound concentrations that do not elicit MT changes or cytotoxicity in mammalian cells. In light of these in vitro results, these TPPs hold promise as candidate anti-schistosomal agents. The next critical step in the evaluation and development of these compounds as candidate treatments for schistosomiasis is to demonstrate the tolerability and in vivo efficacy of one or more TPP candidates. Towards this end, we propose two aims: (1) Complete structure activity/property relationship studies (SAR/SPR) of 30-50 TPPs through their design, synthesis and in vitro phenotypic evaluation vs. S. mansoni. This will be followed up with pharmacokinetic (PK) analysis of the most promising compounds (3–6) that meet all pre-defined selection criteria for in vitro anti- schistosomal activity, selectivity and “drug-like” physicochemical properties. (2) After the resynthesis of the top 1-3 performing compounds, define their maximum tolerated doses in vivo and subsequently determine their efficacy in a mouse model of S. mansoni infection. The proposed project will provide evidence of a correlation between in vitro and in vivo anti-schistosomal activity, and identify one or more lead structures for future studies that will focus specifically on lead optimization and an understanding of the mechanism of action.