P218

P218 is a novel, potent, and selective small molecule inhibitor of *Plasmodium falciparum* bifunctional dihydrofolate reductase-thymidylate synthase (PfDHFR-TS), the clinically validated target for antifolate antimalarial drugs. It was discovered through a structure-informed drug discovery process to overcome resistance seen with older antifolates like pyrimethamine. P218 exhibits strong *in vitro* and *in vivo* activity against both wild-type and pyrimethamine-resistant strains of *P. falciparum*, including quadruple mutant forms[1][2][3][4]. Its mechanism involves tight binding to the active site of PfDHFR, employing a slow-on/slow-off mode that prolongs target residence time compared to existing drugs[5][7]. Preclinical studies show high efficacy at low doses and favorable safety profiles; early clinical trials indicate good tolerability in humans[1][5]. The compound is being developed primarily as a chemoprotective agent for malaria, with particular interest in long-acting injectable formulations suitable for vulnerable or migratory populations[8].

Other names

3-(2-{3-[(2,4-Diamino-6-ethylpyrimidin-5-yl)oxy]propoxy}phenyl)propanoic acid