The Acquired Immunodeficiency Syndrome (AIDS) continues to be a major health problem in the United States and around the world. In the United States nearly 80% of patients with HIV will die because of opportunistic infections, with Pneumocystis carinii pneumonia the most frequent infection. Although significant strides have been made in the treatment and prophylaxis of P. carinii pneumonia there is clearly a need for new, better tolerated drugs active against Pneumocystis. Likewise, new therapeutic agents are needed for several other important AIDS related pathogens including: Cryptococcus neoformans, Cryptosporidium parvum, Mycobacterium avium, Toxoplasma gondii, Mycobacterium tuberculosis, and Candida albicans. Together with P. carinii, these organisms account for the majority of morbidity and mortality in AIDS patients. The dicationic class of molecules, related to pentamidine, have demonstrated activity against each of these opportunistic pathogens. The studies outlined for this renewal application stem from the convincing data generated during the first two years of funding that show a strong correlation between DNA binding, topoisomerase inhibition and antimicrobial activity of dicationic molecules. We will exploit this relationship in the design and synthesis of more potent and less toxic compounds. In addition, we will employ new strategies toward the development of oral active dicationic molecules. The studies will consist of a highly integrated effort carried out at four separate academic institutions [North Carolina at Chapel Hill (UNC-CH), Georgia State University (GSU), Auburn University (AU), University of Duke University (DU)] and one corporate partner, Pharm-Eco (PE). The synthetic tasks will be divided between GSU and UNC. The group at GSU will work primarily with molecules that include furan and pyrimidine ring systems as spacers between the cationic centers, while the UNC-CH group will focus on benzimidazoles, carbazoles and alpha, omega, dioxyalkanes. The choice of these spacing units is based on our previous studies. The molecular genetics studies into the mechanism of action of the compounds against C. neoformans will be carried out at Duke University. The biophysical studies, including the molecular modeling studies, will be carried out at GSU. The biochemical studies will be performed at UNC-CH. Antimicrobial testing will be undertaken at UNC-CH, AU and DU. Support chemistry (batch chemistry and the synthesis of intermediates) and additional financial support for early phase preclinical development will be the responsibility of PE. Such an integrated approach will maximize the chances of achieving our final goal, the development of new agents for the treatment of AIDS- Associated opportunistic infections.
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