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A series of 4-amino 2-anilinoquinazolines optimized for activity against the most lethal malaria parasite of humans, Plasmodium falciparum, were evaluated for activity against other human Plasmodium parasites and related apicomplexans that infect humans and animals. Four of the most promising compounds from the 4-amino 2-anilinoquinazoline series were equally as effective against the asexual blood stages of the zoonotic P. knowlesi suggesting they could also be effective against the closely related P. vivax, another important human pathogen. The 2-anilinoquinazoline compounds were also potent against an array of P. falciparum parasites resistant to clinically available anti-malarial compounds although slightly less so than the drug sensitive 3D7 parasite line. The apicomplexan parasites Toxoplasma gondii, Babesia bovis and Cryptosporidium parvum were less sensitive to the 2-anilinoquinazoline series with an EC50 generally in the low micromolar range suggesting the yet to be discovered target of these compounds is absent or highly divergent in non-Plasmodium parasites. The 2-anilinoquinazoline compounds act as rapidly as chloroquine in vitro and when tested in rodents displayed a half-life that contributed to the compound’s capacity to clear P. falciparum blood stages in a humanized mouse model. At a dose of 50 mg/kg adverse effects to the humanized mice were noted and evaluation against a panel of experimental high-risk off targets indicated some potential off target activity. Further optimization of the 2-anilinoquinazoline antimalarial class will concentrate on improving in vivo efficacy and addressing adverse risk.