Novel Purine Chemotypes with Activity against Plasmodium falciparum and Trypanosoma cruzi

Martinez-Peinado, Nieves; Lorente-Macías, Álvaro; García-Salguero, Alejandro; Cortes-Serra, Nuria; Fenollar-Collado, Ángel; Ros-Lucas, Albert; Gascon, Joaquim; Pinazo, Maria-Jesus; Molina, Ignacio J.; Unciti-Broceta, Asier; Díaz-Mochón, Juan J.; Pineda de las Infantas y Villatoro, María J.; Izquierdo, Luis; Alonso-Padilla, Julio

doi:10.3390/ph14070638

Open AccessArticle

Novel Purine Chemotypes with Activity against Plasmodium falciparum and Trypanosoma cruzi

by

Nieves Martinez-Peinado

¹

,

Álvaro Lorente-Macías

^2,3,4

,

Alejandro García-Salguero

¹,

Nuria Cortes-Serra

¹

,

Ángel Fenollar-Collado

¹,

Albert Ros-Lucas

¹

,

Joaquim Gascon

¹,

Maria-Jesus Pinazo

¹

,

Ignacio J. Molina

³,

Asier Unciti-Broceta

⁴

,

Juan J. Díaz-Mochón

²,

María J. Pineda de las Infantas y Villatoro

^2,*

,

Luis Izquierdo

^1,*

and

Julio Alonso-Padilla

^1,*

¹

Barcelona Institute for Global Health (ISGlobal), Hospital Clínic—University of Barcelona, 08036 Barcelona, Spain

²

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

³

Institute of Biopathology and Regenerative Medicine, Centre for Biomedical Research, University of Granada, Avda. del Conocimiento s/n, 18100 Granada, Spain

⁴

Cancer Research UK Edinburgh Centre, Institute of Genetics & Cancer, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XR, UK

^*

Authors to whom correspondence should be addressed.

Pharmaceuticals 2021, 14(7), 638; https://doi.org/10.3390/ph14070638

Submission received: 28 May 2021 / Revised: 24 June 2021 / Accepted: 26 June 2021 / Published: 1 July 2021

(This article belongs to the Collection Drug Discovery and Development for Tropical Diseases (TDs))

Download

Browse Figures

Review Reports Versions Notes

Abstract

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 (IC₅₀ = 19.19 µM) and 76 (IC₅₀ = 18.27 µM) were the most potent against P. falciparum. On the other hand, 6D (IC₅₀ = 3.78 µM) and 34 (IC₅₀ = 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.

Keywords: Plasmodium falciparum; Trypanosoma cruzi; purine metabolism; purine derivatives; pyrimidine analogs; phenotypic assays; cytotoxicity assays

Graphical Abstract

Share and Cite

MDPI and ACS Style

Martinez-Peinado, N.; Lorente-Macías, Á.; García-Salguero, A.; Cortes-Serra, N.; Fenollar-Collado, Á.; Ros-Lucas, A.; Gascon, J.; Pinazo, M.-J.; Molina, I.J.; Unciti-Broceta, A.; et al. Novel Purine Chemotypes with Activity against Plasmodium falciparum and Trypanosoma cruzi. Pharmaceuticals 2021, 14, 638. https://doi.org/10.3390/ph14070638

AMA Style

Martinez-Peinado N, Lorente-Macías Á, García-Salguero A, Cortes-Serra N, Fenollar-Collado Á, Ros-Lucas A, Gascon J, Pinazo M-J, Molina IJ, Unciti-Broceta A, et al. Novel Purine Chemotypes with Activity against Plasmodium falciparum and Trypanosoma cruzi. Pharmaceuticals. 2021; 14(7):638. https://doi.org/10.3390/ph14070638

Chicago/Turabian Style

Martinez-Peinado, Nieves, Álvaro Lorente-Macías, Alejandro García-Salguero, Nuria Cortes-Serra, Ángel Fenollar-Collado, Albert Ros-Lucas, Joaquim Gascon, Maria-Jesus Pinazo, Ignacio J. Molina, Asier Unciti-Broceta, and et al. 2021. "Novel Purine Chemotypes with Activity against Plasmodium falciparum and Trypanosoma cruzi" Pharmaceuticals 14, no. 7: 638. https://doi.org/10.3390/ph14070638

APA Style

Martinez-Peinado, N., Lorente-Macías, Á., García-Salguero, A., Cortes-Serra, N., Fenollar-Collado, Á., Ros-Lucas, A., Gascon, J., Pinazo, M.-J., Molina, I. J., Unciti-Broceta, A., Díaz-Mochón, J. J., Pineda de las Infantas y Villatoro, M. J., Izquierdo, L., & Alonso-Padilla, J. (2021). Novel Purine Chemotypes with Activity against Plasmodium falciparum and Trypanosoma cruzi. Pharmaceuticals, 14(7), 638. https://doi.org/10.3390/ph14070638

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Menu

Novel Purine Chemotypes with Activity against Plasmodium falciparum and Trypanosoma cruzi

Abstract

Share and Cite

Article Metrics

Article Access Statistics

Further Information

Guidelines

MDPI Initiatives

Follow MDPI