Identification and Profiling of a Novel Diazaspiro[3.4]octane Chemical Series Active against Multiple Stages of the Human Malaria Parasite Plasmodium falciparum and Optimization Efforts

A novel diazaspiro[3.4]octane series was identified from a Plasmodium falciparum whole-cell high-throughput screening campaign. Hits displayed activity against multiple stages of the parasite lifecycle, which together with a novel sp(3)-rich scaffold provided an attractive starting point for a hit-to-lead medicinal chemistry optimization and biological profiling program. Structure-activity- relationship studies led to the identification of compounds that showed low nanomolar asexual blood-stage activity (<50 nM) together with strong gametocyte sterilizing properties that translated to transmission-blocking activity in the standard membrane feeding assay. Mechanistic studies through resistance selection with one of the analogues followed by whole-genome sequencing implicated the P. falciparum cyclic amine resistance locus in the mode of resistance.

Automated summary

A novel series of compounds was identified from a high-throughput screening campaign against Plasmodium falciparum, showing activity against multiple stages of the parasite lifecycle and providing a promising starting point for medicinal chemistry optimization and biological profiling. Further studies revealed compounds with low nanomolar asexual blood-stage activity and strong gametocyte sterilizing properties, which translated to transmission-blocking activity in standard assays. Mechanistic studies suggested the involvement of the P. falciparum cyclic amine resistance locus in resistance development.