Ligia F Ceole1, Hirenkumar Gandhi2,3, Luz H Villamizar4, Maurilio J Soares1, Timothy P O'Sullivan2,3,5. 1. Laboratory of Cell Biology, Carlos Chagas Institute/Fiocruz, 81350-010, Curitiba, PR, Brazil. 2. School of Chemistry, University College Cork, Cork, T12 YN60, Ireland. 3. Analytical & Biological Chemistry Research Facility, University College Cork, Cork, T12 YN60, Ireland. 4. Laboratory of Molecular Biology of Trypanosomatids, Carlos Chagas Institute/Fiocruz, 81350-010, Curitiba, PR, Brazil. 5. School of Pharmacy, University College Cork, Cork, T12 YN60, Ireland.
Abstract
AIM: Chagas disease is a tropical disease caused by the hemoflagellate protozoan Trypanosoma cruzi. There is no vaccine for Chagas disease and available drugs (e.g., benznidazole) are effective only during the acute phase, displaying a variable curative activity in the established chronic form of the disease. New leads with high efficacy and better toxicity profiles are urgently required. Materials & methods: A library of novel quinine derivatives was synthesized using Heck chemistry and evaluated against the various developmental forms of T. cruzi. RESULTS AND CONCLUSION: Several novel quinine analogs with trypanocidal activity have been identified with the para-nitro-substituted derivative displaying a submicromolar IC50, which is 83-times lower than quinine and three-times lower than benznidazole. Transmission electron microscopy analysis demonstrated that these compounds induced a marked vacuolization of the kinetoplast of intracellular amastigotes and cell-derived trypomastigotes.
AIM: Chagas disease is a tropical disease caused by the hemoflagellate protozoan Trypanosoma cruzi. There is no vaccine for Chagas disease and available drugs (e.g., benznidazole) are effective only during the acute phase, displaying a variable curative activity in the established chronic form of the disease. New leads with high efficacy and better toxicity profiles are urgently required. Materials & methods: A library of novel quinine derivatives was synthesized using Heck chemistry and evaluated against the various developmental forms of T. cruzi. RESULTS AND CONCLUSION: Several novel quinine analogs with trypanocidal activity have been identified with the para-nitro-substituted derivative displaying a submicromolar IC50, which is 83-times lower than quinine and three-times lower than benznidazole. Transmission electron microscopy analysis demonstrated that these compounds induced a marked vacuolization of the kinetoplast of intracellular amastigotes and cell-derived trypomastigotes.
Authors: Melissa F Adasme; Sarah Naomi Bolz; Lauren Adelmann; Sebastian Salentin; V Joachim Haupt; Adriana Moreno-Rodríguez; Benjamín Nogueda-Torres; Verónica Castillo-Campos; Lilián Yepez-Mulia; José A De Fuentes-Vicente; Gildardo Rivera; Michael Schroeder Journal: Int J Mol Sci Date: 2020-11-20 Impact factor: 5.923