Ferrocenyl-chloroquine/mefloquine-carbohydrate Conjugates in Malaria

Malaria is a widespread parasitic disease that affects a large population. Four species of the human infecting parasite are known, plasmodium falciparum being the most lethal of these. It is estimated that 2 billion people have been exposed to the parasite. It is estimated that yearly 300-500 million new cases are reported, and between 1 and 2.7 million people die from the infection. Historically, malaria is found in tropical areas, including the poorest countries. Although the majority of cases originate in Africa, Southeast Asia, India, and parts of South America, the disease is now threatening to spread into more temperate zones of the world and global warming would certainly facilitate this reach. Currently, no commercially available vaccine for malaria exists, and drug resistance is becoming rampant.

The need for different categories of anti-malarials, active against the resistant strains, has risen. Unfortunately, scant funding for a poor person’s disease has led to insufficient research for novel drugs and treatments for malaria and to our work with UBC’s Neglected Global Diseases Initiative - NGDI. Some alternative drugs are being investigated, but are either costly or have adverse side effects, such as toxicity.

An attractive area of research for new malarial treatment is directed metal conjugates, particularly those of known anti-malarial drugs. Ferrocene has several properties that have facilitated its investigation for potential biological applications. Typically, organometallic compounds are sensitive to moisture and air, but ferrocene belongs to a unique group thereof whose members are stable under both aqueous and aerobic conditions. The small size, relative lipophilicity, easy chemical modification, and accessible one electron oxidation potential of ferrocene make it an attractive reporter moiety and an intriguing pharmaceutical vector. Ferrocenoyl carbohydrate conjugates have potential as metalloantimalarials. Combining the ferrocene moiety with a glucose derivative and with known antimalarial drugs is a novel approach for developing targeted therapy. The ferrocene moiety has proven to be a successful addition to known malaria therapeutics, increasing efficacy towards chloroquine resistant strains of the parasite. As well, glucose uptake and metabolism in infected erythrocytes is elevated at all stages of the parasite’s life cycle and glucose consumption has been a target in anti-malarial research. The hypothesis of this work is that ferrocenyl-chloroquine/mefloquine-carbohydrate conjugates have the potential to retain activity in chloroquine resistant parasite strains, and to have increased efficacy by targeting infected cells. This work studies the cytotoxicity and anti-plasmodial activity of several ferrocene conjugates, and includes the synthesis and characterization of numerous new conjugates.

With Dr. M. J. Adam of TRIUMF, we have published some preliminary studies showing that ferrocenyl carbohydrate conjugates exhibit some selective anti-malarial activity - glucose uptake and metabolism in infected erythrocytes is elevated at all stages of the parasite’s life cycle. The main goal of the project is to synthesize new ferrocenyl-chloroquine/mefloquine-carbohydrate conjugates that are inexpensive to produce, have activity in chloroquine-resistant parasites strains and that will have increased efficacy by targeting infected cells.