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 sp3-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.