Novel Pentamidine Congeners as Anti-opportunistic and Anti-parasitic Agents

本研究的主要目标是开发新型构象限制性喷他脒同系物作为治疗卡氏肺孢子虫肺炎（PCP）的潜在临床候选药物，PCP是艾滋病患者中最常见的机会性感染。喷他脒被广泛用于治疗艾滋病相关的PCP，尽管它有大量的严重不良反应。喷他脒是一种芳香族双脒，是一种柔性分子，可以呈现多种相互转化的构象。我们假设药物的构象灵活性允许其与不同的大分子结合，这可能至少部分地解释了药物的治疗作用和毒性作用。喷他脒的确切作用机制尚不清楚。根据我们的假设，我们认为治疗 通过合成构象受限的喷他脒同系物，可以将喷他脒的作用与其毒性作用分离，它们代表了新的抗机会和抗寄生虫剂。由于喷他脒已显示出令人印象深刻的抗寄生虫活性，因此还将对所提出的化合物进行针对布氏锥虫和杜氏利什曼原虫寄生虫的评价。第一个目的是合成具有改善的功效和降低的毒性的构象限制的喷他脒同系物。这项工作的基本原理是，我们已经开发了几种构象限制的喷他脒同系物，有效的抗P，卡氏和抗寄生虫剂。与喷他脒相比，这些药剂中的几种更有效且毒性更低。第二个目的是测试化合物的体外活性 针对卡氏肺孢子虫、布氏锥虫和杜氏利什曼原虫在建立的体外筛选系统的合作基础上。将测定这些化合物的DNA结合亲和力，以研究抗PCP和抗寄生虫活性与DNA结合亲和力之间的关系。还将使用上皮样人肺细胞系（A549）评价化合物的人体毒性。第三个目标是合成多克量的最有前途的化合物，用于我们的合作者使用PCP和锥虫的动物模型进行体内功效和毒性研究。我们将设计和合成前药，以优化药物输送和口服生物利用度。这项研究将提供新的抗PCP和抗寄生虫剂，更有效，毒性更低，临床上有用的药物，可以克服目前使用的药物方案的缺点。

The primary goal of this research is to develop novel conformationally restricted pentamidine congeners as potential clinical candidates in the treatment of Pneumocystis carinii pneumonia (PCP), an opportunistic infection most commonly seen in patients with AIDS. Pentamidine is widely used in the treatment of AIDS related PCP despite its vast array of serious adverse reactions. Pentamidine, an aromatic bis-amidine, is a flexible molecule and can assume a number of interconvertible conformations. We hypothesize that the conformational flexibility of the drug allows it to bind to different macromolecules and this may account at least in part, for the therapeutic as well as the toxic actions of the drug. The precise mechanism(s) of action of pentamidine is not known. Based on our hypothesis, we believe that the therapeutic actions of pentamidine can be separated from its toxic actions through the synthesis of conformationally restricted congeners of pentamidine and they represent novel antiopportunistic and antiparasitic agents. Since pentamidine has shown impressive antiparasitic activity, the proposed compounds will also be evaluated against Trypanosoma brucei and Leishmania donovani parasites. The first aim is to synthesize conformationally restricted pentamidine congeners with improved efficacy and reduced toxicity. The rationale for this work is that we have developed several conformationally restricted pentamidine congeners that are effective anti-P, carinii and antiparasitic agents. Several of these agents were more potent and less toxic compared to pentamidine. The second aim is to test the in vitro activity of the compounds against Pneumocytis carinii, Trypanosoma brucei and Leishmania donovani in established in vitro screening systems on a collaborative basis. The DNA binding affinity of these compounds will be determined in order to investigate the relationship between the anti-PCP and antiparasitic activity versus DNA binding affinity. The compounds will also be evaluated for their human toxicity using an epithelioid human lung cell line (A549). The third aim is to synthesize in multi-gram quantities the most promising compounds for in vivo efficacy and toxicity studies using animal models of PCP and trypanosomiasis by our collaborators. We will design and synthesize pro-drugs in order to optimize drug delivery and oral bioavailability. This study will provide novel anti-PCP and antiparasitic agents that are more potent, less toxic, clinically useful agents that may overcome the drawbacks of currently used drug regimens.