Malaria remains a major public health problem. With the loss of antimalarials to resistance, the malaria burden will likely continue for decades. New antimalarial scaffolds are crucial to avoid cross-resistance. Here, we present the first structure based virtual screening using the β-haematin crystal as a target for new inhibitor scaffolds by applying a docking method. The ZINC15 database was searched for compounds with high binding affinity with the surface of the β-haematin crystal using the pyRx Virtual Screening tool. top-ranked compounds predicted to interact with β-haematin were submitted to a second screen applying in silico toxicity and drug-likeness predictions using osiris DataWarrior. fifteen compounds were purchased for experimental testing. An NP-40 mediated β-haematin inhibition assay and parasite growth inhibition activity assay were performed. the benzoxazole moiety was found to be a promising scaffold for further development, showing intraparasitic haemozoin inhibition using a cellular haem fractionation assay causing a decrease in haemozoin in a dose dependent manner with a corresponding increase in exchangeable haem. A β-haematin inhibition hit rate of 73% was found, a large enrichment over random screening, demonstrating that virtual screening can be a useful and costeffective approach in the search for new haemozoin inhibiting antimalarials.

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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.