Optimization of 2‑Anilino 4‑Amino Substituted Quinazolines into Potent Antimalarial Agents with Oral in Vivo Activity

Novel
antimalarial therapeutics that target multiple stages of
the parasite 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 comparable
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 multidrug
resistant strain of P. falciparum and arrest parasites
at the ring phase of the asexual stage and also gametocytogensis.
Finally, we show that the lead compounds are orally efficacious in
a 4 day murine model of malaria disease burden.