Abstract

A program of research is outlined which will develop the observation that primaquine, an 8-aminoquinoline antiprotozoal agent, has potential for chemotherapy of Pneumocystis carinii infections. Modern drug design strategies, including computer-aided molecular modeling techniques, will be utilized to define the optimum 8-aminoquinolines structures for evaluation as pre-clinical candidates of P. carinii infections. Quinoline ring substituted analogs as well as 8-aminoalkyl side chain analogs will be prepared and evaluated. Structure-activity-relationship analysis will be performed and those 8-aminoquinolines predicted to possess structure for enhanced chemotherapy potential will be identified, prepared and evaluated. Pharmacokinetic parameters will be considered an important contributor to optimum characters for chemotherapy potential. This process will be repeated, if necessary, to define more optimal drug candidates from this class of agents. The candidates with highest potential for development will be selected and analytical methodology developed to monitor the candidate drugs and their expected metabolites in body fluids and tissues.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI035203-02
Application #
3727620
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
1995
Total Cost
Indirect Cost

  Institution

Name
University of Mississippi
Department
Type
DUNS #
City
University
State
MS
Country
United States
Zip Code
38677

  Publications

Nanayakkara, N P Dhammika; Ager Jr, Arba L; Bartlett, Marilyn S et al. (2008) Antiparasitic activities and toxicities of individual enantiomers of the 8-aminoquinoline 8-[(4-amino-1-methylbutyl)amino]-6-methoxy-4-methyl-5-[3,4-dichlorophenoxy]quinoline succinate. Antimicrob Agents Chemother 52:2130-7
Bartlett, M S; Queener, S F; Shaw, M M et al. (1997) In vitro and in vivo models of Pneumocystis carinii. J Eukaryot Microbiol 44:51S
Shaw, M M; McChesney, J D; Nanayakkara, D et al. (1997) Modified 8-aminoquinolines cure mouse Pneumocystis carinii infection. J Eukaryot Microbiol 44:40S
Hong, Y L; Hossler, P; Bartlett, M et al. (1996) Evaluation of sulfa drugs against recombinant Pneumocystis carinii dihydropteroate synthetase and in vivo. J Eukaryot Microbiol 43:40S
Lane, B; Hossler, P; Bartlett, M et al. (1996) Sulfa resistance in mouse-derived Pneumocystis carinii. J Eukaryot Microbiol 43:39S