Abstract Current malaria treatments are threatened by drug resistance and new drugs are urgently needed. In a phenotypic screen for new antimalarials, we identified ( S )-SW228703 (( S )-SW703), a tyrosine amide with asexual blood and liver stage activity and a fast-killing profile. Resistance to ( S )-SW703 is associated with mutations in Plasmodium falciparum cyclic amine resistance locus ( Pf CARL) and P. falciparum acetyl CoA transporter ( Pf ACT), similarly to several other compounds that share features such as fast activity and liver-stage activity. Compounds with these resistance mechanisms are thought to act in the ER, though their target(s) are unknown. The tyramine of ( S )-SW703 is shared with some reported Pf CARL-associated compounds; however, we observed that strict S-stereochemistry was required for activity of ( S )-SW703, suggesting differences in mechanism of action or binding mode. ( S )-SW703 provides a new chemical series with broad activity on multiple life-cycle stages and a fast-killing mechanism of action, available for lead optimization to generate new treatments for malaria.

A fast-killing tyrosine amide ((<i>S</i>)-SW228703) with blood and liver-stage antimalarial activity associated with the Cyclic Amine Resistance Locus (<i>Pf</i>CARL)

A fast-killing tyrosine amide ((S)-SW228703) with blood and liver-stage antimalarial activity associated with the Cyclic Amine Resistance Locus (PfCARL)