Trypanocidal properties, structure–activity relationship and computational studies of quinoxaline 1,4-di-N-oxide derivatives

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Abstract

Pyrazole and propenone quinoxaline derivatives were tested against intracellular forms of Leishmania peruviana and Trypanosoma cruzi. Both series were tested for toxicity against proliferative and non-proliferative cells. The pyrazole quinoxaline series was quite inactive against T. cruzi; however, the compound 2,6-dimethyl-3-f-quinoxaline 1,4-dioxide was found to inhibit 50% of Leishmania growth at 8.9 μM, with no impact against proliferative kidney cells and with low toxicity against THP-1 cells and murine macrophages. The compounds belonging to the propenone quinoxaline series were moderately active against T. cruzi. Among these compounds, two were particularly interesting, (2E)-1-(7-fluoro-3-methyl-quinoxalin-2-yl)-3-(3,4,5-trimethoxy-phenyl)-propenone and (2E)-3-(3,4,5-trimethoxy-phenyl)-1-(3,6,7-trimethyl-quinoxalin-2-yl)-propenone. The former possessed selective activity against proliferative cells (cancer and parasites) and was inactive against murine peritoneal macrophages; the latter was active against Leishmania and inactive against the other tested cells. Furthermore, in silico studies showed that both series respected Lipinski’s rules and that they confirmed a linear correlation between trypanocidal activities and LogP. Docking studies revealed that compounds of the second series could interact with the poly (ADP-ribose) polymerase protein of Trypanosoma cruzi.

Graphical abstract

Main interactions between (2E)-1-(7-fluoro-3-methyl-quinoxalin-2-yl)-3-(3,4,5-trimethoxy-phenyl)-propenone and the active site of T.cruzi catPARP-1 homologous protein.

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Research highlights

► (2E)-1-(7-fluoro-3-methyl-quinoxalin-2-yl)-3-(3,4,5-trimethoxy-phenyl)-propenone is selectively active against proliferative cells (cancer and Leishmania) and inactive against murine peritoneal macrophages. ► (2E)-3-(3,4,5-trimethoxy-phenyl)-1-(3,6,7-trimethyl-quinoxalin-2-yl)-propenone is selectively active against Leishmania and inactive against the other proliferative cells. ► in silico studies show that these compounds could interact with the poly (ADP-ribose) polymerase protein of Trypanosoma cruzi.

Introduction

Leishmaniasis is a parasitic disease, which can appear in visceral, cutaneous and mucocutaneous forms, affecting millions of people throughout the world. The drugs used are antimonials, pentamidine and amphotericin B, all of which are toxic and must be administered via injection. In addition, this therapy is expensive and has a limited therapeutic range (Davis et al., 2004). Although miltefosine has been found to be active when administered by oral route in the treatment of mucosal leishmaniasis in Bolivia (Soto et al., 2008), it is not very active in the other forms of leishmaniasis (Yardley et al., 2005).

Chagas disease is also a public health problem, although restricted to the American continent. The acute phase of the disease causes severe myocarditis or meningitis, while the chronic form may induce fatal heart failure (Nwaka and Hudson, 2006). Only a few drugs are commercially available, but they are not consistently effective; in addition, all of them have toxic side effects (Urbina and Docampo, 2003). As a result, the search for new trypanocidal compounds remains essential in order to control and prevent the dramatic consequences of these parasitosis. In a previous study (Burguete et al., 2008), we showed that quinoxaline could open the way to finding innovative anti-leishmanial drug candidates. In addition, Iwashita et al. (2005) and Ishida et al. (2006) showed that quinoxaline derivatives are potent inhibitors of poly ADP-ribose polymerase (PARP), an enzyme implicated in the DNA repair (Alarcón de la Lastra et al., 2007). Therefore, we determined the structure–activity relationship of trimethoxy-phenyl quinoxaline derivatives on murine peritoneal macrophages (MPM) infected by amastigotes of Leishmania peruviana (MHOM/PE/LCA08) and on VERO cells infected by Trypanosoma cruzi (Tulahuen C4). We also carried out an in silico study on their ADME properties, putative mode of union and principal interactions with PARP-1, a poly (ADP-ribose) polymerase protein of T. cruzi.

Section snippets

Synthesis of quinoxaline and quinoxaline 1,4-di-N-oxide derivatives

IR spectra were performed on Thermo Nicolet FT-IR Nexus Euro (Madison, USA) using Potassium bromide pellets; the frequencies are expressed in cm−1. The 1H Nuclear magnetic resonance spectra were recorded on a Bruker 400 Ultrashield™ (Bruker BioSpin GmbH, Rheinstetten, Germany), using Tetramethylsilane as internal standard and with deuterated chloroform and dimethyl-d6 sulfoxide (DMSO-d6) as solvents; the chemical shifts are reported in ppm (d), and the coupling constant (J) values are given in

Biological activities

In this study, eleven quinoxaline derivatives were tested for their activity against various cell lines: three cancer cell lines (Vero, LLc-Mk2 kidney epithelial cell, and THP-1 monocytic cells), one nontumorogenic cell line (Murine Peritoneal Macrophages: MPM) and two parasites: L. peruviana (MHOM/PE/LCA08), responsible for cutaneous and sometimes mucocutaneous New World leishmaniasis; and T. cruzi (Tulahuen C4), responsible for Chagas disease. Compounds and biological activities of series 1

Conclusion

Against T. cruzi, series 1 was almost inactive while the second series presents moderate activity. Against Leishmania, compounds 1d and 2f showed interesting selective activity without toxicity against proliferative kidney cells, and low toxicity against THP-1 and MPM. With regard to the second series (2a–f), the hydrophilicity–lipophilicity balance seems to play an important role. The more hydrophilic the substituents were, the higher the toxicity and antiparasitic activity were (2e and 2b);

Acknowledgments

The authors thank Professor Jorge Arévalo of the Instituto de Medicina Tropical ‘‘Alexander von Humboldt” of the Universidad Peruana Cayetano Heredia for providing THP-1 cells and L. peruviana LCA 08 strain. We thank Dr. J. Carlos Aponte, Dr. Jose Correa and Msc Peio Irigoyen for their constructive criticisms. The authors gratefully acknowledge the ‘‘Oficina de Cooperación de la Embajada de Bélgica” for funding Master Scholarship to Denis Castillo.

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