Pneumocystis carinii pneumonia (PCP) is an opportunistic infection affecting patients with acquired immunodeficiency syndrome (AIDS) and patients with malignancies such as acute lymphotic leukemia. The drug of choice for the treatment of PCP in AIDS patients is pentamidine. Pentamidine however causes a number of side effects among which is hepatitis. Since alcohol consumption is a major risk factor for cirrhosis, alcoholic AIDS patients are at a greater risk of death from liver damage. There is therefore the need for safer and less hepatotoxic drugs for treatment of PCP in this population of AIDS patients. Pentamidine is known to interact with a number of macromolecules in protozoa. However the type of macromolecular interaction that leads to the anti-PCP action of the drug is yet to be established. Pentamidine is a flexible molecule and as such can assume a number of interconvertible conformations. We hypothesize that this conformational flexibility allows pentamidine 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 the therapeutic actions of pentamidine from it's toxic actions via conformation-biological activity relationship studies. To test this hypothesis, conformationally restricted analogues related to pentamidine will be synthesized and tested for anti-PCP activity as well as toxicity in a rat model of the disease. This study could generate new non-hepatotoxic drugs for treatment of PCP. Our long term goal is to develop new safer agents for the treatment of AIDS related PCP.
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