The existing drug regimens for AIDS-related OI are only of limited use due to their high toxic effects and due to the fact that the pathogens develop resistance to them with great ease. This project aims to develop clinically useful alternatives to prevent and cure OIs, especially Pneumocystis carinii pneumonia.This work is based on the hypothesis that compounds with oxidoredox properties can damage many pathogens which cause OIs. Subsequently, four pharmacophores were selected and incorporated into molecules having widely varying structures, which resulted in the identification of one compound carrying each of the pharmacophores having activity against P. carinii equal or better than the existing drugs in in vitro assays. Synthesis of modified versions/analogs of these four lead compounds will be undertaken to minimize their toxicity and to enhance their efficacy. Control of their cost of production by optimizing the yields of the syntheses, which use very few steps, will also be of concern. Molecular modeling will be employed extensively as a tool to aid in the design, synthesis and characterization of these analogs. In vivo studies on mice of the active leads, in progress, are reported to have identified the metallomacrocycle pharmacophore with efficacy comparable to that of the drug combination currently in use, namely, trimethoprim/sulfamethoxazole. Synthesis of the analogs of this lead compound will therefore be of the highest priority.The Indiana University Subcontract will provide culture and animal models of P. carinii. The culture model will grow P. carinii. The animal models will provide P. carinii organisms for culture inocula and for testing the effectiveness of selected drugs in vivo. Cultures will be evaluated by microscopic counting and an ELISA P. carinii antigen quantitation method. Animal models, available for organism production and determining efficacy of compounds in vivo include both dexamethasone immunosuppressed rat and mouse models and an immunologically immunosuppressed mouse model. The scientific laboratory core will use methods developed by the investigators at Indiana University.
