Disulfide-Reductase Inhibitors as Chemotherapeutic Agents: The Design of Drugs for Trypanosomiasis and Malaria

Viewed globally, parasitic diseases such as malaria and Chagas' cardiopathy pose an increasing threat to human health and welfare. Recognition of this problem and the challenge of synthesizing a quinine‐like antimalarial agent sparked off the development of the chemical industry about 100 years ago. Our contribution deals with aspects of drug design, a young branch of pharmaceutical chemistry. As drug targets the flavoenzyme, glutathione reductase, and the recently discovered parasite enzyme, trypanothione reductase, were chosen. Based on the knowledge of the structure of these molecules, the modeling of enzyme inhibitors as potential chemotherapeutic agents against parasites has become possible. In addition, biochemical and clinical observations are considered since chemical principles of biological evolution can serve as guidelines for the pharmaceutical chemists. The picture shows two erythrocytes destroyed by malaria parasites. In the center of the photograph a parasite is just leaving its host cell through the ruptured cell membrane. Its target could be a neighboring healthy erythrocyte. The designation “scourge of mankind” has been attached to parasitic infections such as Chagas' heart disease, sleeping sickness, and malaria. In many countries of the world they lead to human misery and massive socio‐medical problems. Several approaches are possible for the design of chemotherapeutic agents that can interfere as enzyme inhibitors with the metabolism of parasites. For instance, structural motifs of an enzyme and its natural substrates can be expolited to control the kinetics of the enzyme–substrate interactions, and thus substrate analogues can influence the enzyme as inhibitors at various stages of the catalytic cycle. The results may be irreversible inhibition, destabilization of the enzyme's structure, or an alteration of its substrate specificity. Glutathione reductase and trypanothione reductase are target enzymes for this strategy of drug design in the fight against tropical diseases.