Membrane active chelators as novel anti-African trypanosome and anti-malarial drugs

• Published in: Parasitology international 2013-10, Vol.62 (5), p.461-463
• Main Authors: Grab, Dennis J, Nenortas, Elizabeth, Bakshi, Rahul P, Nikolskaia, Olga V, Friedman, Jonathan E, Shapiro, Theresa A
• Format: Article
• Language: English
• Subjects: African trypanosomiasis; Animals; antimalarials; Antimalarials - pharmacology; blood serum; cell membranes; chelating agents; chemotherapy; cytotoxicity; dose response; DP-460; DP-99; drug resistance; drugs; Egtazic Acid - analogs & derivatives; Egtazic Acid - chemistry; Egtazic Acid - pharmacology; Gastroenterology and Hepatology; humans; hydrophobicity; In vitro study; Infectious Disease; malaria; mechanism of action; Membrane active chelator (MAC); metal ions; Molecular Structure; parasites; parasitology; Plasmodium; Plasmodium - drug effects; Plasmodium falciparum; Trypanocidal Agents - pharmacology; Trypanosoma - drug effects; Trypanosoma brucei; Trypanosoma brucei brucei; viability
• ISSN: 1383-5769; 1873-0329
• DOI: 10.1016/j.parint.2013.06.009

Abstract Malaria ( Plasmodium spp.) and human African trypanosomiasis ( Trypanosoma brucei spp.) are vector borne, deadly parasitic diseases. While chemotherapeutic agents for both diseases are available, difficulty in disease eradication and development of drug resistance require that new therapies targeting unexplored pathways or exploiting novel modes of action be developed. Intracellular Plasmodium and extracellular Trypanosoma brucei may have unique and essential requirements for divalent metal ions, beyond that deemed physiological for the host. Membrane Active Chelators (MACs), biologically active only in a hydrophobic lipid environment, are able to bind metal ions at elevated non-physiological concentrations in the vicinity of cell membranes. A dose–response relationship study using validated viability assays revealed that two MAC drugs, DP-b99 and DP-460, were cytotoxic for these parasites in vitro . The 50% effective concentration (EC50 ) values for DP-b99 and DP-460 were 87 μM and 39 μM for Trypanosoma brucei brucei and 21 μM and 28 μM for erythrocytic Plasmodium falciparum , respectively. Furthermore, drug potency was maintained for at least 24 h in serum containing medium at 37 °C. While the exact mechanism of action of MACs against intracellular malaria and extracellular African trypanosome parasites has yet to be determined, their potential as antiparasitic agents warrants further investigation.