Dual parasiticidal activities of phthalimides: synthesis and biological profile against Trypanosoma cruzi and Plasmodium falciparum

Paulo André Teixeira de Moraes Gomes, Marcos Veríssimo de Oliveira Cardoso, Ignes Regina dos Santos, Fabiano Amaro de Sousa, Juliana Maria da Conceição, Vanessa Gouveia de Melo Silva, Denise Duarte, Raquel Pereira, Rafael Oliveira, Fátima Nogueira, Luiz Carlos Alves, Fabio André Brayner, Aline Caroline da Silva Santos, Valéria Rêgo Alves Pereira, Ana Cristina Lima Leite

Research output: Contribution to journalArticlepeer-review

Abstract

Chagas disease and malaria are two neglected tropical diseases (NTDs) that prevail in tropical and subtropical regions in 149 countries. Chagas is also present in Europe, the US and Australia due to immigration of asymptomatic infected individuals. In the absence of an effective vaccine, the control of both diseases relies on chemotherapy. However, the emergence of parasite drug resistance is rendering currently available drugs obsolete. Hence, it is crucial to develop new molecules. Phthalimides, thiosemicarbazones, and 1,3-thiazoles have been used as scaffolds to obtain antiplasmodial and anti-Trypanosoma cruzi agents. Herein we present the synthesis of 24 phthalimido-thiosemicarbazones (3 a–x) and 14 phthalimido-thiazoles (4 a–n) and the corresponding biological activity against T. cruzi, Plasmodium falciparum, and cytotoxicity against mammalian cell lines. Some of these compounds showed potent inhibition of T. cruzi at low cytotoxic concentrations in RAW 264.7 cells. The most active compounds, 3 t (IC50=3.60 μM), 3 h (IC50=3.75 μM), and 4 j (IC50=4.48 μM), were more active than the control drug benznidazole (IC50=14.6 μM). Overall, the phthalimido-thiosemicarbazone derivatives were more potent than phthalimido-thiazole derivatives against T. cruzi. Flow cytometry assay data showed that compound 4 j was able to induce necrosis and apoptosis in trypomastigotes. Analysis by scanning electron microscopy showed that T. cruzi trypomastigote cells treated with compounds 3 h, 3 t, and 4 j at IC50 concentrations promoted changes in the shape, flagella, and surface of the parasite body similar to those observed in benznidazole-treated cells. The compounds with the highest antimalarial activity were the phthalimido-thiazoles 4 l (IC50=1.2 μM), 4 m (IC50=1.7 μM), and 4 n (IC50=2.4 μM). Together, these data revealed that phthalimido derivatives possess a dual antiparasitic profile with potential effects against T. cruzi and lead-like characteristics.

Original languageEnglish
Pages (from-to)2164-2175
Number of pages12
JournalChemmedchem
Volume15
Issue number22
DOIs
Publication statusPublished - 18 Nov 2020

Keywords

  • Phthalimide
  • Plasmodium falciparum
  • Thiazole
  • Thiosemicarbazone
  • Trypanosoma cruzi

UN Sustainable Development Goals (SDGs)

  • SDG 3 - Good Health and Well-Being

Fingerprint Dive into the research topics of 'Dual parasiticidal activities of phthalimides: synthesis and biological profile against Trypanosoma cruzi and Plasmodium falciparum'. Together they form a unique fingerprint.

Cite this