NEW AGENTS FOR PNEUMOCYSTIS CARINII PNEUMONIA

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Pneumocystis carinii pneumonia (PCP) is the most common serious opportunistic infection in patients with acquired immunodeficiency syndrome (AIDS) and as a major cause of mortality in these patients. Pentamidine is one of the drugs of choice widely used for the treatment of AIDS-related PCR despite its high incidence of serious side effects. Therefore, the is a critical need for more effective and less toxic anti-PCP agents. Pentamidine is a flexible molecule and can assume a number of interconvertible conformations. The precise mechanism of anti-PCP action of pentamidine is unknown. We hypothesize that the conformational flexibility of pentamidine allows it to bind to different macromolecules and this may account at least in part, for the therapeutic as well as toxic actions of the drug. It may therefore, be possible to separate these actions by a conformation-biological activity relationship study. To test these hypothesis, we propose to conduct the following studies: a) design and synthesize new conformationally restricted analogues related to pentamidine; b) determine the pKa values of the synthesized compounds; c) evaluate the compounds for in vitro anti-PCP activity and toxicity in an animal model of the disease; e) study the interactions of the proposed pentamidine analogues with DNA using molecular modeling techniques and by measuring thermal denaturation temperatures. The information gained will be valuable not only in determining the mechanism(s) of action of the pentamidine analogues, but may also result in the development of a more effective and safer anti-PCR agent.