The synthesis of parasitic cysteine protease and trypanothione reductase inhibitors.
The presence of parasitic cysteine proteases and trypanothione reductase in the parasitic protozoa of the genus Trypanosoma and Leishmania has made these enzymes attractive targets for the development of antitrypanosomal and antileishmanial agents. Furthermore, the presence of cysteine proteases in Plasmodium falciparum has presented additional opportunities for the development of chemical scaffolds that could potentially be utilized against all of the aforementioned parasites. While previous reviews on parasitic cysteine proteases and trypanothione reductase covered various aspects, none emphasized the chemistry behind the synthesis of described inhibitors. This review focuses on recent developments in the synthesis of low-molecular weight inhibitors of these enzymes with a bearing on the human diseases of leishmaniasis, malaria and trypanosomiasis. Only those inhibitors whose synthesis has been described in the open literature during the period 1993-mid 2002 have been highlighted. The review thus excludes what may be in the patent literature. Inhibitors synthesized using combinatorial and/or parallel synthesis chemistry as well as polymer-assisted synthesis methodologies have been deliberately omitted from this review because they are a subject of a separate and focused review.
Chibale
Kelly
K
Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa. chibale@science.uct.ac.za
Musonda
Chitalu C
CC
D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D007891:Leishmania / Q000187:drug effects; D008956:Models, Chemical; D015394:Molecular Structure; D008970:Molecular Weight; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors*; D014345:Trypanosoma / Q000187:drug effects
D000981:Antiprotozoal Agents; D015853:Cysteine Proteinase Inhibitors; D004791:Enzyme Inhibitors; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase