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Malaria is among the tropical diseases that cause the most deaths in Africa. Around 500,000 malaria deaths are reported yearly among African children under the age of five. Chloroquine (CQ) is a low-cost antimalarial used worldwide for the treatment of Plasmodium vivax malaria. Due to resistance mechanisms, CQ is no longer effective against most malaria cases caused by P. falciparum. The World Health Organization recommends artemisinin combination therapies for P. falciparum malaria, but resistance is emerging in Southeast Asia and some parts of Africa. Therefore, new medicines for treating malaria are urgently needed. Previously, our group identified the 4-aminoquinoline DAQ , a CQ analog containing an acetylenic bond in its side chain, which overcomes CQ resistance in K1 P. falciparum strains. In this work, the antiplasmodial profile, drug-like properties, and pharmacokinetics of DAQ were further investigated. DAQ showed no cross-resistance against standard CQ -resistant strains (e.g., Dd2, IPC 4912, RF12) nor against P. falciparum and P. vivax isolates from patients in the Brazilian Amazon. Using drug pressure assays, DAQ showed a low propensity to generate resistance. DAQ showed considerable solubility but low metabolic stability. The main metabolite was identified as a mono N -deethylated derivative (DAQ M), which also showed significant inhibitory activity against CQ -resistant P. falciparum strains. Our findings indicated that the presence of a triple bond in CQ -analogues may represent a low-cost opportunity to overcome known mechanisms of resistance in the malaria parasite. [Display omitted] • 4-aminoquinoline antimalarial candidates containing a triple bond did not show in vitro cross-resistance against CQ -resistant strains. • DAQ showed a low propensity to generate resistant mutants in vitro after 90 days of drug pressure. • DAQ was active against Plasmodium falciparum and P. vivax field isolates from Brazilian Amazon. • DAQ M , the main metabolite of DAQ , also potently inhibited both CQ -sensitive and CQ -resistant strains. [ABSTRACT FROM AUTHOR]