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.
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.
