Malaria is one of the most prevalent infectious diseases worldwide and it represents a major global health issue for which new effective chemotherapies are urgently needed. The most successful antimalarial drug for decades was chloroquine, but the widespread emergence of resistant parasites in most endemic areas severely limits its efficacy. First- line antimalarial treatments today are based on artemisinin and related 1, 2, 4-trioxanes;these drugs are highly active and fast acting against chloroquine-resistant malaria, but they are limited by their short plasma half-lives, which results in parasite recrudescence when used as a monotherapy. The World Health Organization currently recommends combination therapies composed of artemisinin and amodiaquine, lumefantrine or mefloquine. Nevertheless, such combinations suffer from problems related to differences in solubility and pharmacokinetics of the individual components, which may compromise the ability of the trioxanes to prevent emergence of drug resistance;therefore new effective antimalarial therapies are needed. Our long-term goal is to discover and develop novel metal-based antimalarial chemotherapeutic agents for the treatment of human disease. Our objective in this proposal is to identify new lead compounds toward ruthenium-derived drugs for the treatment of malaria and to elucidate their mechanisms of action. Our central hypothesis is that combining ruthenium with chloroquine, a trioxane, or chloroquine and a trioxane in a single molecule will lead to new multifunctional compounds effective for specific targets in resistant malaria parasites, as a result of the physicochemical characteristics of the organometallic structure. This research is based upon our previous work and data from other researchers, strongly indicating that metal-based approach is a promising alternative for the development of non-toxic chemotherapeutic agents against resistant malaria.
The specific aims of the project are: 1. to synthesize and evaluate the antimalarial potential and toxicity of covalently linked Ru-chloroquine complexes targeting heme aggregation. 2. To synthesize and evaluate Ru-trioxane and Ru-(bis) trioxane complexes as potential non-toxic antimalarial agents acting by radical alkylation mechanisms. 3. To synthesize and evaluate hybrid Ru-chloroquine-trioxane complexes as potential non-toxic antimalarial agents acting by dual mechanisms.

Public Health Relevance

Malaria is one of the most prevalent infectious diseases worldwide;300-500 million people become infected and close to a million die of malaria each year, mostly children under 5 years of age. The most important issue in the treatment of malaria today is the widespread emergence of resistance to commonly used drugs. This proposal presents a promising alternative toward the development of novel and effective metal-based antimalarial therapies and it opens important avenues of research for understanding their mechanisms of action.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Enhancement Award (SC1)
Project #
5SC1GM089558-04
Application #
8528622
Study Section
Special Emphasis Panel (ZGM1-MBRS-X (CH))
Program Officer
Fabian, Miles
Project Start
2010-09-01
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
4
Fiscal Year
2013
Total Cost
$299,980
Indirect Cost
$108,910
Name
Brooklyn College
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
620127691
City
New York
State
NY
Country
United States
Zip Code
11210
Iniguez, Eva; Sanchez, Antonio; Vasquez, Miguel A et al. (2013) Metal-drug synergy: new ruthenium(II) complexes of ketoconazole are highly active against Leishmania major and Trypanosoma cruzi and nontoxic to human or murine normal cells. J Biol Inorg Chem 18:779-90
Demoro, Bruno; Sarniguet, Cynthia; Sanchez-Delgado, Roberto et al. (2012) New organoruthenium complexes with bioactive thiosemicarbazones as co-ligands: potential anti-trypanosomal agents. Dalton Trans 41:1534-43
Martinez, Alberto; Carreon, Teresia; Iniguez, Eva et al. (2012) Searching for new chemotherapies for tropical diseases: ruthenium-clotrimazole complexes display high in vitro activity against Leishmania major and Trypanosoma cruzi and low toxicity toward normal mammalian cells. J Med Chem 55:3867-77
Glans, Lotta; Ehnbom, Andreas; de Kock, Carmen et al. (2012) Ruthenium(II) arene complexes with chelating chloroquine analogue ligands: synthesis, characterization and in vitro antimalarial activity. Dalton Trans 41:2764-73
Navarro, Maribel; Castro, William; Higuera-Padilla, Angel R et al. (2011) Synthesis, characterization and biological activity of trans-platinum(II) complexes with chloroquine. J Inorg Biochem 105:1684-91
Martinez, Alberto; Suarez, Javier; Shand, Tiffany et al. (2011) Interactions of arene-Ru(II)-chloroquine complexes of known antimalarial and antitumor activity with human serum albumin (HSA) and transferrin. J Inorg Biochem 105:39-45
Navarro, Maribel; Castro, William; Martinez, Alberto et al. (2011) The mechanism of antimalarial action of [Au(CQ)(PPh(3))]PF(6): structural effects and increased drug lipophilicity enhance heme aggregation inhibition at lipid/water interfaces. J Inorg Biochem 105:276-82