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

本研究的主要目的是开发新的构象限制性喷他脒同源物，作为治疗卡氏肺囊虫肺炎（PCP）的潜在临床候选药物，这是一种最常见于艾滋病患者的机会性感染。喷他脒被广泛用于治疗艾滋病相关的PCP，尽管它有大量严重的不良反应。喷他脒是一种芳香双脒，是一种柔韧的分子，具有多种可相互转换的构象。我们假设，这种药物的构象灵活性允许它与不同的大分子结合，这可能至少部分地解释了这种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。基于我们的假设，我们认为治疗性的

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.