Potent naphthoquinones against antimony-sensitive and -resistant Leishmania parasites: Synthesis of novel α- and nor-α-lapachone-based 1,2,3-triazoles by copper-catalyzed azide–alkyne cycloaddition

• DOI: 10.1016/j.ejmech.2013.02.038
• Publication Date: 2013-03-07T19:17:44Z
• Authors: Tiago T. Guimarães; Maria do Carmo F....; Juliane S. Lanza; Maria N. Melo; Rubens L. do Mont...; Isadora M.M. de Melo; Emilay B.T. Diogo; Vitor F. Ferreira; Celso A. Camara; Wagner O. Valença; Ronaldo N. de Oli...; Frédéric Frézard; Eufrânio N. da Si...
• Keywords: Antimony; Leishmania; Azides; Cycloaddition Reaction; Cell Survival; Antiprotozoal Agents; Drug Resistance; Triazoles; 01 natural sciences; Catalysis; 0104 chemical sciences; 3. Good health; Mice; Parasitic Sensitivity Tests; Species Specificity; Alkynes; Macrophages, Peritoneal; Animals; Leishmania infantum; Cells, Cultured; Copper; Naphthoquinones

Continuing our screening program for novel anti-parasite compounds, we synthesized seven 1,4-naphthoquinones coupled to 1,2,3-triazoles, five nor-β-lapachone-based 1,2,3-triazoles and ten α-lapachone-based 1,2,3-triazoles. These and other naphthoquinonoid compounds were evaluated for their activity against promastigote forms of antimony-sensitive and -resistant strains of Leishmania infantum (syn. Leishmania chagasi) and Leishmania amazonensis. The toxicity of these compounds to mammalian cells was also examined. The substances were more potent than an antimonial drug, with IC50 values ranging from 1.0 to 50.7 μM. Nor-α-lapachone derivatives showed the highest antileishmanial activity, with selectivity indices in the range of 10-15. These compounds emerged as important leads for further investigation as antileishmanial agents. Additionally, one of these compounds exhibited cross-resistance in Sb-resistant Leishmania and could provide a molecular tool for investigating the multidrug resistance mechanisms in Leishmania parasites.