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

• Squaric acid/4-aminoquinoline conjugates were synthesized.
• Compounds were evaluated against papain, falcipain-2 and Pf W2.
• Three compounds had higher in vitro potency than chloroquine.
• The most active compounds were noncytotoxic.

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.

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