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

这项研究的主要目标是开发新的构象受限的戊烷胺同系物，作为治疗卡氏肺孢子虫肺炎(PCP)的潜在临床候选药物。PCP是一种最常见于艾滋病患者的机会性感染。尽管有一系列严重的不良反应，五烷胺仍被广泛用于艾滋病相关的PCP的治疗。五烷双胺是一种芳香族双脒，是一种灵活的分子，可以呈现多种可相互转化的构象。我们假设药物的构象灵活性允许它与不同的大分子结合，这可能至少部分解释了药物的治疗和毒性作用。确切的作用机理(S)尚不清楚。基于我们的假设，我们认为治疗 通过合成构象受限的五烷双胺同系物，可将其毒性作用与其作用分离，是一种新型的抗机会性和抗寄生虫剂。由于戊二甲双胺显示出令人印象深刻的抗寄生虫活性，建议的化合物也将被评估对布鲁氏锥虫和杜氏利什曼原虫的抗寄生虫。第一个目标是合成构象受限的戊烷胺同系物，以提高疗效和降低毒性。这项工作的基本原理是，我们已经开发了几种构象受限的戊烷胺同系物，它们是有效的抗P、Carinii和抗寄生虫剂。这些药剂中有几种与五烷胺相比效力更强，毒性更低。第二个目的是测试化合物的体外活性。 在合作的基础上建立了针对卡氏肺孢子炎、布氏锥虫和杜氏利什曼原虫的体外筛选系统。将测定这些化合物的DNA结合亲和力，以研究抗PCP与抗寄生虫活性与DNA结合亲和力之间的关系。还将使用上皮样人类肺细胞系(A549)评估这些化合物的人体毒性。第三个目标是由我们的合作者利用五氯酚和锥虫病的动物模型，以多克数量合成最有希望的化合物，用于体内疗效和毒性研究。我们将设计和合成前体药物，以优化药物释放和口服生物利用度。这项研究将提供新的抗PCP和抗寄生虫药，它们是更有效、毒性更低、临床有用的药物，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.