Design, Synthesis and Testing of Novel Antimalarial
Abstract
The purpose of this project was to enhance the effectiveness of the class of chemicals known as isoquinolines against malaria, a disease causing over one million deaths each year. Many drugs are available to combat the parasite responsible for these deaths, but resistance has been recorded to nearly all of them. There is therefore a need for new antimalarial drugs against which the parasite is not resistant. As a contribution to the development of a new drug, this project involved modification of a lead compound, with known antimalarial properties, to enhance its effectiveness against the disease. The lead compound was a potent folate antagonist, a widely used class of antimalarial with significant resistance problems. Recent research had suggested that the lead compound acted against the disease through a distinct, unknown mechanism, in addition to that of folate antagonism. Six target compounds were designed to increase the activity by this unknown antimalarial mechanism, while removing activity via the folate mechanism. These novel target compounds were 1,7-disubstituted isoquinolines. The design included use of a 3D computer-generated pharmacophore model, which described the structural requirements for maximum antimalarial activity by the unidentified mechanism. Reduction of the folate antagonist activity relied upon published data describing the structural requirements for folate antagonism. The antimalarial activity of the newly designed compounds was thus expected to be mediated by the unknown mechanism. As such, the compounds should be effective even against parasite resistant to folate antagonists. Toxicity and synthesis issues were considered when the compounds were designed. A seven step synthesis was designed by which each of the six target compounds were prepared. A significant proportion of the project involved execution of these syntheses in the laboratory.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 05, 2006
- Accession Number
- ADA452979
Entities
People
- Marshall M. Hoffman
Organizations
- United States Naval Academy