. The long term goal of this AREA proposal is to elucidate the molecular target for the anti- Pneumocystis carinii activity of aromatic diamidines, and to use this knowledge to develop new chemotherapeutic agents. The short term goal of the proposal is to determine if the activity of the aromatic diamidines is mediated by sequence-selective binding to the minor groove of DNA. Pentamidine is one of the drugs of choice for treating Pneumocystis carinii pneumonia (PCP) which afflicts between 60 - 80% of AIDS patients in the U. S. Geometric isomers have been synthesized as semirigid congeners of pentamidine for investigating the mechanism of action of the drug. In vitro DNA-binding studies and footprinting studies showed that the cis isomer binds with higher affinity to DNA than does the trans isomer and that the binding affinity correlates with the in vitro anti-P. carinii activity. These compounds were, however, equipotent in an in vivo model of PCP. Based on these results it is hypothesized that: i) DNA is the molecular target for the anti-P. carinii activity of aromatic diamidines; and ii) the geometric isomers are subject to stereoselective pharmacokinetic processes resulting in greater in vivo exposure to the trans isomer and equipotent efficacy as compared to the cis isomer. These hypotheses will be tested by synthesizing compounds with varying binding affinities for DNA. The invitro and invivo anti-P. carinii activities will be determined. Pharmacokinetic studies will be carried out and the results analyzed to determine if there is a statistically significant correlation between in vitro DNA binding affinity, in vitro anti-P. carinni activity, and in vivo exposure and anti-P. carinii activity of the aromatic diamidines to establish DNA as their molecular target of action.
| Donkor, Isaac O; Huang, Tien L; Tao, Bin et al. (2003) Trypanocidal activity of conformationally restricted pentamidine congeners. J Med Chem 46:1041-8 |
| Donkor, I O; Assefa, H; Rattendi, D et al. (2001) Trypanocidal activity of dicationic compounds related to pentamidine. Eur J Med Chem 36:531-8 |
| Tao, B; Huang, T L; Sharma, T A et al. (1999) Novel bisbenzamidines and bisbenzimidazolines as noncompetitive NMDA receptor antagonists. Bioorg Med Chem Lett 9:1299-304 |
| Donkor, I O; Clark, A M (1999) In vitro antimicrobial activity of aromatic diamidines and diimidazolines related to pentamidine. Eur J Med Chem 34:639-43 |
