Fast-Killing Tyrosine Amide ((S)‑SW228703) with Blood- and Liver-Stage Antimalarial Activity Associated with the Cyclic Amine Resistance Locus (PfCARL)

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 the Plasmodium falciparum cyclic amine resistance locus (PfCARL) and P. falciparum acetyl CoA transporter (PfACT), 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 targets are unknown. The tyramine of (S)-SW703 is shared with some reported PfCARL-associated compounds; however, we observed that strict S-stereochemistry was required for the activity of (S)-SW703, suggesting differences in the mechanism of action or binding mode. (S)-SW703 provides a new chemical series with broad activity for multiple life-cycle stages and a fast-killing mechanism of action, available for lead optimization to generate new treatments for malaria.当前疟疾治疗方案正面临耐药性威胁，亟需开发新型抗疟药物。在针对新型抗疟药物的表型筛选（phenotypic screen）中，我们发现了(S)-SW228703（(S)-SW703）——一种具备无性血液阶段（asexual blood stage）与肝期（liver stage）抗疟活性、且具有快杀特性（fast-killing profile）的酪氨酸酰胺（tyrosine amide）类化合物。(S)-SW703的耐药性与恶性疟原虫环状胺耐药位点（Plasmodium falciparum cyclic amine resistance locus, PfCARL）以及恶性疟原虫乙酰辅酶A转运蛋白（Plasmodium falciparum acetyl CoA transporter, PfACT）的突变相关，这与其他若干兼具快速活性与肝期活性等特征的化合物的耐药机制类似。尽管此类化合物的具体作用靶点尚未被探明，但具备上述耐药机制的化合物被推测作用于内质网（Endoplasmic Reticulum, ER）。(S)-SW703所携带的酪胺（tyramine）结构与部分已报道的PfCARL相关化合物一致；但我们的研究发现，(S)-SW703的活性严格依赖于S型立体构型，这提示其作用机制（mechanism of action）或结合模式（binding mode）存在差异。(S)-SW703代表了一类全新的化学系列，其对疟原虫多个生命周期阶段均具有广谱活性，且具备快杀的作用机制，可用于先导化合物优化（lead optimization）以开发新型疟疾治疗方案。