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The 4-aminoquinoline drugs, such as chloroquine (CQ), amodiaquine or piperaquine, are still commonly used for malaria treatment, either alone (CQ) or in combination with artemisinin derivatives. We previously described the excellent in vitro activity of a novel pyrrolizidinylmethyl derivative of 4-amino-7-chloroquinoline, named MG3, against P. falciparum drug-resistant parasites. Here, we report the optimized and safer synthesis of MG3, now suitable for a scale-up, and its additional in vitro and in vivo characterization. MG3 is active against a panel of P. vivax and P. falciparum field isolates, either alone or in combination with artemisinin derivatives. In vivo MG3 is orally active in the P. berghei, P. chabaudi, and P. yoelii models of rodent malaria with efficacy comparable, or better, than that of CQ and of other quinolines under development. The in vivo and in vitro ADME-Tox studies indicate that MG3 possesses a very good pre-clinical developability profile associated with an excellent oral bioavailability, and low toxicity in non-formal preclinical studies on rats, dogs, and non-human primates (NHP). In conclusion, the pharmacological profile of MG3 is in line with those obtained with CQ or the other quinolines in use and seems to possess all the requirements for a developmental candidate. Agency for Science, Technology and Research (A*STAR) Published version This work was also supported by the Ministero dell’Istruzione, dell’Università e della Ricerca (PRIN) Projects 2010C2LKKJ_006, 20154JRJPP_004, the Global Health Program of the Bill & Melinda Gates Foundation (Grant OPP1040394), the Ministero degli Affari Esteri e della Cooperazione Internazionale (PGR00949), the A*STAR Infectious Disease labs, the Horizontal Programme on Infectious Diseases under the Agency for Science, Technology and Research (A*STAR, Singapore) (LR), and SMRU supported by The Wellcome Trust of Great Britain, as part of the Oxford Tropical Medicine Research Programme of the Wellcome Trust-Mahidol University