TY - JOUR
T1 - Trypanocidal properties, structure-activity relationship and computational studies of quinoxaline 1,4-di-N-oxide derivatives
AU - Estevez, Yannick
AU - Quiliano, Miguel
AU - Burguete, Asunción
AU - Cabanillas, Billy
AU - Zimic, Mirko
AU - Málaga, Edith
AU - Verástegui, Manuela
AU - Pérez-Silanes, Silvia
AU - Aldana, Ignacio
AU - Monge, Antonio
AU - Castillo, Denis
AU - Deharo, Eric
N1 - Funding Information:
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.
PY - 2011/4
Y1 - 2011/4
N2 - 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 Log. P. Docking studies revealed that compounds of the second series could interact with the poly (ADP-ribose) polymerase protein of Trypanosoma cruzi.
AB - 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 Log. P. Docking studies revealed that compounds of the second series could interact with the poly (ADP-ribose) polymerase protein of Trypanosoma cruzi.
KW - Leishmania peruviana
KW - Quinoxaline 1,4-di-N-oxide derivatives
KW - Trypanosoma cruzi
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U2 - 10.1016/j.exppara.2011.01.009
DO - 10.1016/j.exppara.2011.01.009
M3 - Article
C2 - 21272583
AN - SCOPUS:79952360113
SN - 0014-4894
VL - 127
SP - 745
EP - 751
JO - Experimental Parasitology
JF - Experimental Parasitology
IS - 4
ER -