Synthesis of novel quinine analogs and evaluation of their effects on Trypanosoma cruzi

Ceole, Ligia F.; Gandhi, Hirenkumar; Villamizar, Luz H.; Soares, Maurilio J.; O'Sullivan, Timothy P.

Synthesis of novel quinine analogs and evaluation of their effects on Trypanosoma cruzi

Files

8470-Accepted.pdf(1.54 MB)

Accepted version

Date

2018-02

Authors

Ceole, Ligia F.

Gandhi, Hirenkumar

Villamizar, Luz H.

Soares, Maurilio J.

O'Sullivan, Timothy P.

Publisher

Future Science: Newlands Press

Published Version

10.4155/fmc-2017-0184

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.

Keywords

Chagas disease , Heck coupling , Kinetoplast vacuolization , Quinine , Trypanocides , Trypanosoma cruzi , Ultrastructure

Citation

Ceole, L. F., Gandhi, H., Villamizar, L. H., Soares, M. J. and O'Sullivan, T. P. (2018) 'Synthesis of novel quinine analogs and evaluation of their effects on Trypanosoma cruzi', Future Medicinal Chemistry, 10(4), pp. 391-408. doi: 10.4155/fmc-2017-0184