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 wholegenome sequencing implicated the P. falciparum cyclic amine resistance locus in the mode of resistance.

A series of 2,4-disubstituted imidazopyridines, originating from a SoftFocus Kinase library, was identified from a high throughput phenotypic screen against the human malaria parasite Plasmodium falciparum. Hit compounds showed moderate asexual blood stage activity. During lead optimization, several issues were flagged such as cross-resistance against the multi-drug resistant K1 strain, in vitro cytotoxicity and cardiotoxicity, and were addressed through structureactivity and structure-property relationship studies. Pharmacokinetic properties were assessed in mouse for compounds showing desirable in vitro activity, selectivity window over cytotoxicity and microsomal metabolic stability. Frontrunner compound 37 showed good exposure in mice combined with good in vitro activity against the malaria parasite which translated into in vivo efficacy in the P. falciparum NOD-scid IL-2Rγ null (NSG) mouse model. Preliminary mechanistic studies suggest inhibition of hemozoin formation as a contributing mode of action.

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