Synthesis and structure-activity relationship of 3-phenylquinoxaline 1,4-di-N-oxide derivatives as antimalarial agents.
As a continuation of our research and with the aim of obtaining new antimalarial agents, new series of 3-phenylquinoxaline 1,4-di-N-oxide derivatives have been synthesized following the classical Beirut reaction. Antiplasmodial activity was evaluated in vitro against Plasmodium falciparum by the incorporation of [3H]-hypoxanthine. Cytotoxicity was tested in KB cells by AlamarBlue assay. Twenty-one of the 60 compounds that were assayed against 3D7 (CQ-sensitive) showed enough activity to be also evaluated against K1 (CQ-resistant) strain. Ten of them were shown to be more active than chloroquine in the resistant strain. The most interesting compounds are 7-(methyl or methoxy)-3-(4'-fluoro or chloro)phenylquinoxaline-2-carbonitrile 1,4-di-N-oxides because of their low IC50 and their high SI shown for the K1 strain, making them valid new leads.
Vicente
Esther
E
Unidad de Investigación y Desarrollo de Medicamentos, Centro de Investigación en Farmacobiología Aplicada (CIFA), University of Navarra, C/Irunlarrea s/n, 31080 Pamplona, Spain.
Lima
Lidia M
LM
Bongard
Emily
E
Charnaud
Sarah
S
Villar
Raquel
R
Solano
Beatriz
B
Burguete
Asunción
A
Perez-Silanes
Silvia
S
Aldana
Ignacio
I
Vivas
Livia
L
Monge
Antonio
A
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity; D002417:Cattle; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D007624:KB Cells; D010963:Plasmodium falciparum / Q000187:drug effects; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D013329:Structure-Activity Relationship
D000962:Antimalarials; D011810:Quinoxalines; C003282:quindoxin