Promising lead compounds for novel antiprotozoals

Abstract

Malaria and human African trypanosomiasis (HAT), also known as sleeping sickness, are devastating diseases caused by infection with the protozoan parasites of the Plasmodia and Trypanosoma genera, respectively. The diseases infect millions of people. HAT, caused by infection with Trypanosoma brucei, is a complex disease and represents a major cause of morbidity and mortality in sub-Saharan Africa, where it is endemic and an estimated 70 million people are at risk of contracting it. Several epidemics of HAT occurred during the last century, but a combination of vector control, disease surveillance and early drug treatment of those infected caused the disease to almost disappear by the mid-1960s. Over the following 2–3 decades the disease re-emerged, but recent control efforts have again reduced its incidence, annual cases totaling an estimated 50 000–70 000. HAT has two distinct forms (gambiense and rhodesiense) depending on the parasite involved, each form having two specific stages. HAT is fatal if left untreated, with treatment depending on the stage of the disease. Drugs for the early-stage (pentamidine and suramin) are well tolerated, easier to administer and more effective. Drugs used for the latestage (melarsoprol, and eflornithine which is ineffective for the acute rhodesiense form) have to cross the blood–brain barrier. They are toxic (particularly melarsoprol), often causing severe and sometimes fatal side effects, and have to be administered under costly medical supervision. Consequently, the swift development and introduction of safer, more effective, easy-to-use and affordable drugs will be instrumental in helping to achieve recent initiatives aimed at eliminating the disease as a public health problem. Unlike HAT, which is restricted to Africa, malaria is widespread globally, with an estimated 3.5 billion people at risk of contracting the disease, 1.3 billion of whom are at high risk. Massive recent global initiatives to combat the disease, integrating vector control, prevention and treatment, have resulted in significant progress. Nevertheless, some 243 million cases occurred in 2008, resulting in an estimated 863 000 deaths, almost 90% of which were in Africa. 1 Many anti