This project addresses the broad area of translational science to develop drugs for malaria. There are no effective vaccines for human malaria and the efficacy of the available drugs, which are not free of toxicity, is declining as resistance emerges. Thus, there is a strong impetus to discover new drugs for malaria, which will have enormous impact on human health, scientific advancement in antimalarial research and extramural funding opportunities from from public and/or private research organizations (e.g., NIH, MMV).
The main objective of this project is to develop anti-malarial drugs based on a recent discovery by the PI of cyclen-quinoline analogs as potent (both in vitro and in vivo) antimalarial agents against chloroquine-resistant and chloroquine-sensitive malarial parasites. Both improved lead as well as better synthetic technique for the existing lead will be developed applying the knowledge based structure activity relastionship and organic synthesis techniques. Thus a series of newer cyclen bisquinoline analogs and their Fe (III)-complexes will be synthesized. The compounds will be analyzed for in vitro antimalarial activity to selct 4 most potent compounds. These will be further screened for in vivo antimalarial activity in mice model. In addition, the existing most potent cyclen-bisquinoline lead structure will be analyzed for its single dose curative ability in the mice model, which is an important criteria to consider it as a clinical candidate. In vitro microsomal stability study will also be performed to address important PK/PD parameters.
In the long term, in vivo toxicology and oral bioavailability as well as hERG assay to predict cardiac toxicity, which are considered important preclinical evaluations, will also be conducted.
The projet will involve wide range of research opportunity in the area of biomedical sciences. Considering the overall research opportunity, the generation of scientific knowledge, involvement of a wide range of technologies, the infected populations and the resulting economic burdens, the impact of this project will be major.
This project addresses discovery of drugs to treat malaria, a neglected tropical disease that causes about 515 million cases each year killing 1-3 million people. Current US military personnel remain susceptible to malaria just like veterans of wars. Moreover, it will expose the undergraduate/Pharm.D. students to a highly significant research activity in the area of biomedical sciences emphasizing public health problem.