Evaluation of the leishmanicidal and cytotoxic effects of inhibitors for microorganism metabolic pathway enzymes.
Chemotherapy for leishmaniosis a neglected parasitic disease, is based on few drugs, which are toxic and present resistance issues. Efforts for the development of new therapies are essential for the control of leishmaniasis. Metabolic pathway enzymes are promising targets for new drugs against parasites. The search for effective drugs against key enzymes can take advantage of the similarities between metabolic pathways in different microorganisms trypanosomatids Trypanosoma cruzi and Leishmania and fungus Saccharomyces cerevisiae. In this report, leishmanicidal activity of the metabolic pathway enzymes inhibitors (IDs) of dihydroorotate dehydrogenase (DHODH), glyceraldehyde 3-phosphate dehydrogenase and cruzain-cysteine protease from T. cruzi and scitalona-desidratase, adenosine deaminase, succinate dehydrogenase complex II and hydroxynaphthalene reductase from S. cerevisiae was performed on Leishmania amazonensis extracellular promastigotes and amastigotes within macrophages. The most promising compound, ID195, which is a DHODH inhibitor was toxic against promastigotes and was selective for amastigotes over host cells.
Departamento de Biologia Animal, Instituto de Biologia, Universidade Estadual de Campinas, Rua Monteiro Lobato, 13083-862 Campinas, SP, Brazil.
Ademar
A
de Mesquita Barbosa
Departamento de Biologia Animal, Instituto de Biologia, Universidade Estadual de Campinas, Rua Monteiro Lobato, 13083-862 Campinas, SP, Brazil.
Solange
S
Dos Santos Costa
Grupo de Química Medicinal de Produtos Naturais, NEQUIMED-PN, Instituto de Química de São Carlos, Universidade de São Paulo, Av. Trabalhador Sancarlense 400, 13566-590 São Carlos, SP, Brazil.
Josmar Rodrigues
JR
da Rocha
Grupo de Química Medicinal de Produtos Naturais, NEQUIMED-PN, Instituto de Química de São Carlos, Universidade de São Paulo, Av. Trabalhador Sancarlense 400, 13566-590 São Carlos, SP, Brazil.
Carlos Alberto
CA
Montanari
Departamento de Biologia Animal, Instituto de Biologia, Universidade Estadual de Campinas, Rua Monteiro Lobato, 13083-862 Campinas, SP, Brazil. Electronic address: sgiorgio@unicamp.br.
Selma
S
Giorgio
D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007891:Leishmania / Q000187:drug effects* / Q000201:enzymology; D007896:Leishmaniasis / Q000188:drug therapy* / Q000469:parasitology; D008264:Macrophages / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000201:enzymology
D000981:Antiprotozoal Agents; D004791:Enzyme Inhibitors
Dihydroorotate dehydrogenase; Leishmania amazonensis; Leishmaniosis; Metabolic pathway enzymes inhibitors; Trypanosomatids