The major goal of this project is the design and synthesis of novel dicationic molecules for the treatment of AIDS associated opportunistic infections. The proposed project will build on the momentum created by our first two years of funding. During this period we have gained considerable insight into the mechanism of action, toxicity and pharmacokinetics of dicationic compounds. One compound developed in our laboratory for treatment of P. carinii Pneumonia is currently in preclinical trials and scheduled for Phase 1 clinical trials before the end of 1994. In addition, we have demonstrated that these compounds exhibit activity against C. parvum, C. neoformans, C. albicans, and M. tuberculosis. Together these opportunistic pathogens account for the majority of morbidity and mortality in AIDS patients. The development of a single drug for treatment of two or more of these infections would be extremely important in the clinical management of AIDS patients. The design of new compounds will focus on two areas: l) The design of novel structures with improved activity based on the apparent relationship between antimicrobial activity, binding to AT rich minor grooves of DNA and selective inhibition of microbial (over mammalian) Topoisomerases. II) Structural modifications that will greatly increase the capacity for these strongly dicationic molecules to be absorbed from the GI tract. The structures proposed in this Project will complement compounds proposed in Project II (Boykin). The combined productivity of the two synthetic laboratories allows for a wide range of structural modifications leading to a comprehensive structure/activity data base. This will provide an excellent opportunity to sort out mechanism(s) of action against the selected organisms. The design of more potent and less toxic compounds will relay heavily on biochemical and enzymological investigations (Dykstra), biophysical studies and computer modeling (Wilson), molecular biological investigations (Perfect) and antimicrobial studies (Blagburn; Hall; Perfect). The design strategy for improving drug potency will include the following factors: l)radius of curvature 2) placement of the cationic groups 3) hydrogen bonding donors and acceptors facing the DNA surface 4) bulky groups facing away from the DNA surface to enhance inhibition of DNA directed enzymes and 5) extended molecules to cover 6-8 base pairs as compared to 3-4 base pairs. The major approaches to increasing the oral bioavailability of the molecule will include the synthesis of prodrugs and zwitterions. The prodrug approach will focus on the design of molecules that reduce the pKa of the dicationic compounds, thus allowing increased uptake from the gastrointestinal tract. These promolecules would then be metabolized back to the bioactive strongly charged dications. The zwitterion approach will result in neutralization of the cationic groups and concomitant increased absorption from the gut. Successful completion of the proposed work should lead to new orally- active agents for the treatment of a number of important AIDS related opportunistic pathogens.
| 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 |
