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Novel antimalarial therapeutics that target multiple stages of the parasites lifecycle are urgently required to tackle the emerging problem of resistance with current drugs. Here we describe the optimization of the 2-anilino quinazoline class as antimalarial agents. The class, identified from publicly available antimalarial screening data, was optimized to generate lead compounds that possess potent antimalarial activity against P. falciparum parasites equivalent to the known antimalarials, chloroquine and mefloquine. During the optimization process we defined the functionality necessary for activity and improved in vitro metabolism and solubility. The resultant lead compounds possess potent activity against a multi-drug resistant strain of P. falciparum and arrest parasites at the ring phase of the asexual stage and gametocytogensis. Finally, we show that the lead compounds are orally efficacious in a 4 day murine model of malaria disease burden.