Current Topics in Medicinal Chemistry - Volume 2, Issue 11, 2002

This is a general review of currently available antimalarial drugs, these compounds are gathered according with its chemical structure and the biological targets. A great number of these new antimalarial agents are now moving actively in the pipeline from basic science to clinical studies.

Chagas' disease is a major parasitic problem in developing countries in Central and South America. Chemotherapy for such disease is still insufficient and not effective in its chronic part. Many efforts have been made in recent years to know more about possible new biochemical targets to design new selective drugs. This paper reviews old therapeutic approaches -Nifurtimox, Benznidazole and related compounds- and the latest rationally developed drugs that prove to be active against different parasitic forms

Parasitic diseases caused by protozoa as Leishmania, Trypanosome or Plasmodium are responsible for more than three millions deaths annually throughout the developing countries. This review covers recent studies on plant-secondary metabolites isolated from medicinal plants and that have demonstrated moderate to high activity in in vitro and in vivo bioassays against these protozoa. The biological activity of the last promising antiparasitic leads are described.

Trypanosomatids are the causative agents of African sleeping sickness, Chagas' disease and the three forms of leihmaniasis. New drugs against these parasitic protozoa are urgently needed since the currently available chemotherapy is not at all satisfying. One promising approach towards the development of new drugs is based on the design of specific enzyme inhibitors.Trypanosomes and leishmania possess a unique thiol metabolism in which the ubiquitous glutathione / glutathione reductase system is replaced by trypanothione and trypanothione reductase. The dithiol trypanothione is the key molecule for the synthesis of DNA precursors, the homeostasis of ascorbate, the detoxification of hydroperoxides, and the sequestration / export of thiol conjugates. Synthesis and reduction of trypanothione are essential for the maintenance of a reducing intracellular milieu which renders the respective enzymes attractive drug target molecules. Here we present the current state of knowledge of the thiol metabolism of trypanosomatids, comprising the trypanothione / tryparedoxin, thioredoxin, and ovothiol systems of the parasites. The most effective inhibitors of the enzymes known to date, their mode of action, and the (dis)advantages of different types of inhibitors as potential drug candidates will be discussed.

Trypanosoma cruzi, the agent of the American Trypanosomiasis, Chagas Disease, contains cysteine, serine, threonine and metallo proteinases. Aspartic proteinases have not been found so far. The most abundant among these enzymes is cruzipain, a cysteine proteinase expressed as a complex mixture of isoforms by the major developmental stages of the parasite, including some membrane-bound isoforms. The enzyme is an immunodominant antigen in human chronic Chagas disease and seems to be important in the host / parasite relationship. Inhibitors of cruzipain kill the parasite and cure infected mice, thus making the enzyme a very promising target for the development of new drugs against Chagas disease. In addition 30 kDa cathepsin B-like enzymes have been described. Serine peptidases described in the parasite include oligopeptidase B, a member of the prolyl oligopeptidase family involved in Ca2+-signalling during mammalian cell invasion; a prolyl endopeptidase (Tc80), against which inhibitors are being developed, and a serine carboxypeptidase belonging to the S10 family. Metalloproteinases homologous to the gp63 of Leishmania spp. are also present. The proteasome has properties similar to those of other eukaryotes, and its inhibition by lactacystin blocks some differentiation steps in the life cycle of the parasite.