Together with efforts impaired by the COVID-19 pandemic, one of the biggest chalenges in fighting malaria is the spread of drug-resistant parasite strains, with special attention to frontline treatments like artemisinin-based combined therapies (ACTs). This scenario poses the development of novel antimalarial drugs as timely. Considering the lengthy drug discovery process, we used machine learning models to predict the antimalarial potential of molecules using quantitative structure-activity relationships (QSAR). Moreover, with the impracticability in cultivating Plasmodium vivax isolates for long periods, we have employed Plasmodium falciparum and other species as initial screening models for evaluating the potential of those predicted compounds. We have successfully identified a 4-aminoquinoline (LDT-623) with strong antimalarial activity against chloroquine-sensitive (3D7) and multidrug-resistant (Dd2) P. falciparum strains in vitro (EC50: 23 and 37 nM), and also considerably selective towards the parasite compared with COS-7 and HepG2 cells (SI: 21.3 and 54.8). LDT-623 shares few features with chloroquine as both are fast-acting compounds and inhibit β-hematin formation in vitro. Nonetheless, while performing an in vitro transmission-blocking assay in P. berghei model, we found it to be quite singular: LDT-623 was unexpectedly active against sexual stages (EC50: 1.6 µM). Furthermore, looking at this transmission blocking potential, we sought to explore the combination of LDT-623 with a known gametocidal, methylene blue, and found them to be synergistic. This dual activity seen for LDT-623 - inhibition of both asexual stages and ookinetes – is not usually reported for 4-aminoquinolines. Given this, we believe that LDT-623 shares a mode of action not exclusive to that observed for other 4-aminoquinolines. Current work on schizont maturation assays on P. vivax field isolates from the Amazon might answer whether this compound, which has shown to be a valuable tool, could open new avenues for vivax malaria treatment while rekindling the interest in this chemical class.