Novel purine chemotypes with activity against Plasmodium 2 falciparum and Trypanosoma cruzi

Nieves Martinez-Peinado, Alvaro Lorente Macias, Alejandro Garcia-Salbuero, Nuria Cortes-Serra, Angel Fenollar-Collado, Albert Ros-Lucas, Joaquim Gascon, Maria-Jesus Pinazo, Ignacio J. Molina, Asier Unciti-Broceta, Juan J. Díaz-Mochón, Maria J. Pineda de las Infantas y Villatoro, Luis Izquierdo, Julio Alonso-Padilla

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Malaria and Chagas disease, caused by Plasmodium spp. and Trypanosoma cruzi parasites, 25 remain an important global health problem. Available treatments for those diseases present several 26 limitations such as lack of efficacy, toxic side effects and drug resistance. Thus, finding new drugs 27 is urgently needed. The discovery of new drugs may be benefited by considering significant bio-28 logical differences between host and parasites. One of the most striking differences is found in the 29 purine metabolism because most of the parasites are incapable of de novo purine biosynthesis. 30 Herein, we have analyzed the in vitro anti-P. falciparum and anti-T. cruzi activity of a collection of 81 31 purine derivatives and pyrimidine analogs. We firstly used a primary screening at three fixed 32 concentrations (100, 10 and 1 μM) and progressed to dose-response assays those compounds that 33 kept the growth of the parasites < 30% at 100 μM. Then, we performed two different cytotoxicity 34 assays on Vero cells and human HepG2 cells. Finally, compounds specifically active against T. cruzi 35 were tested against intracellular amastigote forms. Purines 33 (IC50 = 19.19 μM) and 76 (IC50 = 18.27 36 μM) were the most potent against P. falciparum. On the other hand, 6D (IC50 = 3.78 μM) and 34 (IC50 37 = 4.24 μM) were identified as hit purines against T. cruzi amastigotes. Moreover, an in silico docking 38 study revealed that P. falciparum and T. cruzi hypoxanthine guanine phosphoribosyltransferase 39 enzymes could be the potential targets of those compounds. Our study identified two novel pu-40 rine-based chemotypes that can be further optimized to generate potent and diversified an-41 ti-parasitic drugs against both parasites.
Original languageEnglish
Early online date1 Jul 2021
Publication statusE-pub ahead of print - 1 Jul 2021

Keywords / Materials (for Non-textual outputs)

  • Plasmodium Falciparum
  • Trypanosome cruzi
  • purine metabolism
  • purine derivatives
  • pyrimidine analogs
  • phenotypic assays
  • cytotoxity assays


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