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.

Graphical abstractIn 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 full-size imageDownload as PowerPoint slide