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Abstract In spite of recent efforts to eradicate malaria in the world, this parasitic disease is still considered a major public health problem, with a total of 216 million cases of malaria and 445,000 deaths in 2016. Artemisinin-based combination therapies remain effective in most parts of the world, but recent cases of resistance in Southeast Asia have urged for novel approaches to treat malaria caused by Plasmodium falciparum. In this work, we present chloroquine analogs that exhibited high activity against sensitive and chloroquine-resistant P. falciparum blood parasites and were also active against P. berghei infected mice. Among the compounds tested, DAQ , a chloroquine analog with a more linear side chain, was shown to be the most active in vitro and in vivo , with low cytotoxicity, and therefore may serve as the basis for the development of more effective chloroquine analogs to aid malaria eradication. Graphical abstract Synthesis of N -(4-(dimethylamino)but-2-enyl)-7-chloro-quinolin-4-amine (DAQ): DAQ , a chloroquine analog with a more linear side chain, exhibited high activity against sensitive and chloroquine-resistant P. falciparum blood parasites and was also active against P. berghei infected mice. Image 1 Highlights • Resistance to recommended malaria therapies by WHO is emerging. • Chloroquine analogs with modified side chains may overcome P. falciparum resistance. • DAQ, a CQ-analog with a more linear side chain, is the most promising tested compound. • DAQ may serve as a lead compound for the design of more effective antimalarials. [ABSTRACT FROM AUTHOR]