The general objective of this research proposal is to select an appropriate candidate compound from a group of oxygenated chalcones with novel activity against malaria parasites for further development into a new antimalarial drug.
The specific objectives are:
* To develop an optimal method for the synthesis of necessary amounts of the appropriate compounds.
* To determine the purity, physicochemical properties and stability of these compounds.
* To examine the in vitro activity of these compounds against different strains at erythrocytic and liver stages of human malaria parasite Plasmodium falciparum.
* To investigate the structure-activity relationship of these compounds.
* To test the activity of selected compounds on the parasite isolates from the blood samples from malaria patients in Colombia.
* To carry out in vivo studies to determine the most appropriate formulation for administration of these compounds.
* To select the most appropriate compound(s), based on their in vitro activity and test them against P. berghei and P. yoelii in murine models and against P. falciparum in Aotus monkeys.
* To investigate the mechanism of action of these compounds on parasite mitochondria.
* To perform studies on absorption, tissue distribution, pharmacokinetics, and pharmaco-dynamics in rats, dogs and monkeys.
The most important expected outcome of this study will be identification of an appropriate oxygenated chalcone for phase 1 studies.
* This study will demonstrate the structural requirements for optimal selectivity and activity for chalcones as antiprotozoal drugs.
* This study will show the activity of these compounds against different strains of P. falciparum in vitro and their activity against different species of Plasmodium in several animal models.
* This study will provide insights into the mechanism of action of the selected compound(s).
* This study will identify the appropriate formulation for in vivo administration of the selected compound(s).
* Development of optimal synthesis methods. A study taking advantage of the methodology developed for Quantitative Structure-Activity Relationships (QSAR) will be utilized to disclose the optimum structure for the antimalarial activity. Based on the outcome of the QSAR analysis new types of compounds will be prepared and evaluated. A procedure for large scale synthesis of the selected compounds will be developed.
* In vitro studies against blood stage Plasmodium falciparum. The effect of a wide range of compounds on different chloroquine sensitive and resistant strains of P. falciparum will be tested using conventional methods. Fifty P. falciparum isolates collected in an endemic region of Colombia will also be studied.
* In vivo studies in murine models. The appropriate compound(s) for the in vivo studies will be selected based on their in vitro activity against P. falciparum. Several mouse models of P. yoelii and P. berghei infection will be used in these studies. The compounds will be administered by different routes and dosages and at different time periods to infected animals. Levels of parasitemia in Giemsa-stained smears and survival of animals will be assessed.
* Studies on the liver stage of P. falciparum. The activity against pre-erythrocytic stages will be tested using in vitro assays with different P. falciparum and in vivo in mice with P. yoelii or P. berghei. The in vivo studies will include i.v. inoculation of sporozoites into mice. The effect of various compounds will be examined by either i.p. or oral administration of selected compounds.
* In vivo studies in Aotus monkeys. The monkeys will be infected and once parasitemia reaches 1.0% they will be treated with the test compound by giving an oral dose of each compound for different time periods. Parasitemia will be determined daily by thick smears and whenever necessary by PCR.
* Studies on the mechanism of action. The effect of these compounds on the ultrastructure by EM and on the function of mitochondria will be carried out. The effect of these compounds on some of the enzymes of the respiratory chain in mitochondria such as fumarate reductase will also be examined.
* Formulation studies. These studies will include preparations based on aqueous solutions by addition of solubility promoting substances e.g. polyalcohol, glycolether and glycolesters or solubilizing agents. Investigation of preparations based on particulate drug delivery systems e.g. oil/water emulsion will also be undertaken.
Funding SchemeCSC - Cost-sharing contracts
2100 København Í
2188 AA Cali