| Autor: |
Martinez-Peinado N; Barcelona Institute for Global Health (ISGlobal), Hospital Clínic-University of Barcelona, 08036 Barcelona, Spain., Lorente-Macías Á; Department of Medicinal & Organic Chemistry and Excellence Research Unit of 'Chemistry Applied to Biomedicine and the Environment', Faculty of Pharmacy, University of Granada, Campus de Cartuja s/n, 18071 Granada, Spain.; Institute of Biopathology and Regenerative Medicine, Centre for Biomedical Research, University of Granada, Avda. del Conocimiento s/n, 18100 Granada, Spain.; Cancer Research UK Edinburgh Centre, Institute of Genetics & Cancer, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XR, UK., García-Salguero A; Barcelona Institute for Global Health (ISGlobal), Hospital Clínic-University of Barcelona, 08036 Barcelona, Spain., Cortes-Serra N; Barcelona Institute for Global Health (ISGlobal), Hospital Clínic-University of Barcelona, 08036 Barcelona, Spain., Fenollar-Collado Á; Barcelona Institute for Global Health (ISGlobal), Hospital Clínic-University of Barcelona, 08036 Barcelona, Spain., Ros-Lucas A; Barcelona Institute for Global Health (ISGlobal), Hospital Clínic-University of Barcelona, 08036 Barcelona, Spain., Gascon J; Barcelona Institute for Global Health (ISGlobal), Hospital Clínic-University of Barcelona, 08036 Barcelona, Spain., Pinazo MJ; Barcelona Institute for Global Health (ISGlobal), Hospital Clínic-University of Barcelona, 08036 Barcelona, Spain., Molina IJ; Institute of Biopathology and Regenerative Medicine, Centre for Biomedical Research, University of Granada, Avda. del Conocimiento s/n, 18100 Granada, Spain., Unciti-Broceta A; Cancer Research UK Edinburgh Centre, Institute of Genetics & Cancer, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XR, UK., Díaz-Mochón JJ; Department of Medicinal & Organic Chemistry and Excellence Research Unit of 'Chemistry Applied to Biomedicine and the Environment', Faculty of Pharmacy, University of Granada, Campus de Cartuja s/n, 18071 Granada, Spain., Pineda de Las Infantas Y Villatoro MJ; Department of Medicinal & Organic Chemistry and Excellence Research Unit of 'Chemistry Applied to Biomedicine and the Environment', Faculty of Pharmacy, University of Granada, Campus de Cartuja s/n, 18071 Granada, Spain., Izquierdo L; Barcelona Institute for Global Health (ISGlobal), Hospital Clínic-University of Barcelona, 08036 Barcelona, Spain., Alonso-Padilla J; Barcelona Institute for Global Health (ISGlobal), Hospital Clínic-University of Barcelona, 08036 Barcelona, Spain. |
| Abstrakt: |
Malaria and Chagas disease, caused by Plasmodium spp. and Trypanosoma cruzi parasites, remain important global health problems. Available treatments for those diseases present several limitations, such as lack of efficacy, toxic side effects, and drug resistance. Thus, new drugs are urgently needed. The discovery of new drugs may be benefited by considering the significant biological differences between hosts and parasites. One of the most striking differences is found in the purine metabolism, because most of the parasites are incapable of de novo purine biosynthesis. Herein, we have analyzed the in vitro anti- P. falciparum and anti- T. cruzi activity of a collection of 81 purine derivatives and pyrimidine analogs. We firstly used a primary screening at three fixed concentrations (100, 10, and 1 µM) and progressed those compounds that kept the growth of the parasites < 30% at 100 µM to dose-response assays. Then, we performed two different cytotoxicity assays on Vero cells and human HepG2 cells. Finally, compounds specifically active against T. cruzi were tested against intracellular amastigote forms. Purines 33 (IC 50 = 19.19 µM) and 76 (IC 50 = 18.27 µM) were the most potent against P. falciparum . On the other hand, 6D (IC 50 = 3.78 µM) and 34 (IC 50 = 4.24 µM) were identified as hit purines against T. cruzi amastigotes. Moreover, an in silico docking study revealed that P. falciparum and T. cruzi hypoxanthine guanine phosphoribosyltransferase enzymes could be the potential targets of those compounds. Our study identified two novel, purine-based chemotypes that could be further optimized to generate potent and diversified anti-parasitic drugs against both parasites. |
