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.

In vitro antiplasmodial activity, cytotoxicity and selectivity parameters of new 3-phenylquinoxaline 1,4-di-N-oxide derivatives are reported. These derivatives emerge as new valid lead-compounds for synthesizing new structures that possess improved activity.Figure optionsDownload as PowerPoint slide