Identification of Fast-Acting 2,6-Disubstituted Imidazopyridines That Are Efficacious in the in Vivo Humanized Plasmodium falciparum NODscidIL2Rγnull Mouse Model of Malaria

Optimization of a chemical series
originating from whole-cell phenotypic
screening against the human malaria parasite, Plasmodium falciparum, led to the identification of two promising 2,6-disubstituted imidazopyridine
compounds, 43 and 74. These compounds exhibited
potent activity against asexual blood stage parasites that, together
with their in vitro absorption, distribution, metabolism, and excretion
(ADME) properties, translated to in vivo efficacy with clearance of
parasites in the PfSCID mouse model for malaria within
48 h of treatment.

针对人类疟原虫，恶性疟原虫（Plasmodium falciparum）的全细胞表型筛选，对化学系列进行了优化，从而鉴定出两种具有潜力的2,6-二取代咪唑并吡啶化合物，分别为化合物43和74。这些化合物对无性期血液阶段寄生虫表现出显著的活性，且结合其在体外吸收、分布、代谢和排泄（ADME）特性，转化为体内疗效，在治疗48小时内即可在恶性疟原虫PfSCID小鼠模型中清除寄生虫。