DRUG DEVELOPMENT FOR SECONDARY INFECTIONS OF AIDS

我们发现，适当取代的山酮与血红素形成配合物，阻止血红素聚合过程，降低血红素的生物利用度。许多寄生虫由于生化不足而需要血红素。我们预测，烷基胺或脒放置在4和5位置的克山酮核将导致加强血红素结合，从而提高药物效力。这些新的二胺类药物对于治疗许多免疫抑制的机会性感染，特别是艾滋病患者具有重要的价值。在这个I期提案中，我们将证明山酮二胺（4,5-取代）比喷他脒更具选择性和毒性，并且对那些对喷他脒敏感的机会性病原体具有活性。我们将制备一系列的山酮二胺，并测试这些化合物作为利什曼原虫、肺囊虫和弓形虫的抑制剂。基于这些体外研究，我们将选择更有价值的化合物（以喷他脒为参照）在这些感染的动物模型中进行测试。建议的商业应用：目前尚无针对许多寄生虫病的有效药物治疗。此外，对于疟疾等疾病，寄生虫表达的多药耐药性正在成为常态。因此，需要新的化合物，并且具有全球重要性。本研究中提出的化合物代表了一类新的抗寄生虫试剂，由于许多不同寄生虫使用的所需血红素获取策略被中断，它们应该有效地对抗大范围的寄生虫病。

We have found that suitably substituted xanthones form complexes with heme and prevent the process of heme polymerization and reduce the bioavailability of heme. Many parasites require heme due to biochemical insufficiencies. We predict that placement of alkylamines or amidines at the 4 and 5 positions of the xanthone nucleus will lead to enhanced heme binding and consequently increased drug potency. These new diamidines will be of significant value for the treatment of many of the opportunistic infections that are found in the immunosuppressed, especially those with AIDS. In this Phase I proposal we will demonstrate that the xanthone diamidines (4,5-substituted) are more selective and less toxic than pentamidine and with activity against those opportunistic pathogens which are susceptible to pentamidine treatment. We will prepare a series of xanthone diamidines and test these compounds as inhibitors of Leishmania, Pneumocystis and Toxoplasma. Based on these in vitro studies we will select compounds of superior value (with pentamidine as a reference) for testing in animal models of these infections. PROPOSED COMMERCIAL APPLICATIONS: Effective drug therapy for many parasitic diseases is not available. In addition for diseases such as malaria, parasite-expressed multidrug resistance is becoming the norm. Consequently new compounds are required and are of global importance. The compounds proposed in this study represent a new class of antiparasitic reagents that should effectively combat a large range of parasitic disease due to the interruption of the required heme-acquisition strategies used by many different parasites.