Squaric acid/4-aminoquinoline conjugates: novel potent antiplasmodial agents

We report the synthesis and structure–activity relationship (SAR) analysis of a series of hybrid compounds containing a squaric moiety conjugated with heterocyclic moieties from well-known antimalarials. This novel series of compounds presents improved antiplasmodial activity compared with the squaric derivatives described in our previous work. Three compounds, 8b (IC50 = 99 nM), 8c (IC50 = 95 nM), and 8d (IC50 = 105 nM) had greater in vitro potency than chloroquine 1 (IC50 = 140 nM) against chloroquine resistant Plasmodium falciparum. In addition, they were noncytotoxic against NIH 3T3 and Hek 293T cells.

This work was supported by Fundação para a Ciência e a Tecnologia (Portugal) through postdoctoral fellowship to S.P.K. (SFRH/BPD/44481/2008), doctoral fellowship to C.J.A.R. (SFRH/BD/69258/2010) and grant PEst-OE/SAU/UI4013/2011. PJR is a Distinguished Clinical Scientist of the Doris Duke Charitable Foundation.