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

2011

Article référencé dans le Web of Science WOS:000288592400004

Estevez Y., Quiliano M., Burguete A., Cabanillas B., Zimic M., Malaga E., Verastegui M., Perez-Silanes S., Aldana I., Monge A., Castillo D., Deharo Eric

Experimental Parasitology, 2011, 127 (4), p. 745-751 ISSN 0014-4894

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 mu M, 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)-p ropenone and (2E)-3-(3,4,5-trimethoxy-phenyl)-1-(3,6,7-trimethyl-quinoxalin-2-yl)-pro penone. 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.

Entomologie médicale / Parasitologie / Virologie [052]

Fonds IRD [F B010053425]

fdi:010053425