DRUG DEVELOPMENT FOR SECONDARY INFECTIONS OF AIDS

我们发现，适当取代的口沙酮与血红素形成络合物，阻止了血红素的聚合过程，降低了血红素的生物利用度。由于生物化学的不足，许多寄生虫需要血红素。我们预测，将烷基胺或胺放置在黄酮核的4和5位将导致血红素结合增强，从而提高药物效力。这些新的二胺类药物将对治疗免疫抑制患者，特别是艾滋病患者的许多机会性感染具有重要价值。在这个第一阶段的提案中，我们将证明，取代的xanthone二胺(4，5-取代)比戊二胺具有更高的选择性和更低的毒性，并且对那些对戊二胺治疗敏感的机会性病原体具有活性。我们将制备一系列的口沙酮二胺类化合物，并测试这些化合物对利什曼原虫、肺孢子虫和弓形虫的抑制作用。在这些体外研究的基础上，我们将选择价值更高的化合物(以戊双胺为参照物)，在这些感染的动物模型中进行测试。建议的商业应用：许多寄生虫病的有效药物治疗尚不存在。除了疟疾等疾病，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所使用的必需的血红素获取策略的中断，这些试剂应该可以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.