Discovery of highly selective 7-chloroquinoline-thiohydantoins with potent antimalarial activity

•Synthesis and antimalarial evaluation of 7-chloroquinoline-thiohydantoins.•Most potent scaffold exhibited IC50 of 39.8 nM with high selectivity.•Studies of β-hematin formation further confirmed their mechanism of action.

A series of C-3 thiourea functionalized β-lactams, β-lactam-7-chloroquinoline conjugates and 7-chloroquinoline-thiohydantoin derivatives were prepared with the aim of probing antimalarial structure–activity relationships. 7-Chlorquinoline-thiohydantoin derivatives were found to be potent inhibitors of cultured Plasmodium falciparum, with the most potent and non-cytotoxic compound exhibiting an IC50 of 39.8 nM. Studies of β-hematin formation suggested that inhibition of haemozoin formation could be primary mechanism of action, with IC50 values comparable to those of chloroquine. Evaluation of cytotoxicity against HeLa cells demonstrated high selective indices.

Graphical abstractSynthesis, antimalarial and cytotoxic evaluation of C-3 functionalized β-lactams, β-lactam-7-chloroquinoline conjugates and 7-chloroquinoline-thiohydantoin derivatives.Figure optionsDownload full-size imageDownload as PowerPoint slide