The goals of Core C remain similar to those of Core D in the current NCDDG grant. We have discovered and confirmed that several aromatic dicationic molecules possess activity against cryptosporidium parvum, a prevalent and important AIDS-associated pathogen. Activity is demonstrable in compounds synthesized in both Dr. Tidwell's and Dr. Boykin's laboratories. Active molecules represent direct analogues of pentamidine, as well as newer dicationic pyrimidines, purines and furans. This progress is exciting and encouraging, and enforces our beliefs that potent cryptosporidicidal compounds, with therapeutic promise, exist within the class of aromatic dicationic molecules. The broad, long-term objective of Core D, therefore, is to identify additional effective dicationic molecules capable of inhibiting development of C. parvum.
Specific aim 1 is to continue to screen compounds synthesized by Tidwell and Boykin using our established suckling murine assay. Several improvements in the enumeration aspects of the assay should allow us to increase our rate of evaluation of compounds.
Specific aim 2 is to provide developmental stages of C. parvum to Dr. Dykstra, whose efforts are pursuant to the identification of molecular targets and modes of activity of effective aromatic dicationic molecules.
| Patrick, D A; Hall, J E; Bender, B C et al. (1999) Synthesis and anti-Pneumocystis carinii pneumonia activity of novel dicationic dibenzothiophenes and orally active prodrugs. Eur J Med Chem 34:575-83 |
| Hall, J E; Kerrigan, J E; Ramachandran, K et al. (1998) Anti-Pneumocystis activities of aromatic diamidoxime prodrugs. Antimicrob Agents Chemother 42:666-74 |
| Tuttle, R H; Hall, J E; Tidwell, R R (1997) High-performance liquid chromatographic assay detects pentamidine metabolism by Fisher rat liver microsomes. J Chromatogr B Biomed Sci Appl 688:319-24 |
| Tidwell, R R; Jones, S K; Naiman, N A et al. (1993) Activity of cationically substituted bis-benzimidazoles against experimental Pneumocystis carinii pneumonia. Antimicrob Agents Chemother 37:1713-6 |
