Evaluation of 4-Amino 2-Anilinoquinazolines against Plasmodium and Other Evaluation of 4-amino 2-anilinoquinazolines against Plasmodium and other apicomplexan parasites in vitro and in a P. falciparum humanized NOD-scid IL2Rynull mouse model of malaria

A series of 4-amino 2-anilinoquinazolines optimized for activity against the most lethal malaria parasite of humans,; Plasmodium falciparum; , was 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 that 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 antimalarial compounds, although slightly less so than against 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 a 50% effective concentration generally in the low micromolar range, suggesting that 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 of body weight, 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.