Phenotypic whole cell screening of a BioFocus DPI SoftFocus library of 40,000 compounds identified more than 200 hits with greater than 80% inhibition at an average primary and retest concentration of 1.82 uM against the malaria parasite Plasmodium falciparum sensitive (3D7) or resistant (Dd2) strains, and which also showed no cytotoxicity at that concentration. The library of 40,000 compounds represented more than 200 scaffolds that had primarily been designed as potential kinase inhibitors, G-Protein Coupled Receptor (GPCR) antagonists or ion channel modulators. Representatives of active series were selected for resynthesis and/or confirmatory testing of the actives against Plasmodia and cytotoxicity. Several of these series offered the combination of novelty, potential clean pharmacology, in vitro antiplasmodial potency, ADME/physicochemical properties and in vivo activity to yield potential lead compounds.Hit triage, hit to lead and lead optimization campaigns will be described.

Hit to lead and lead optimization of antimalarial whole cell hits from a SoftFocus library

243rd National Meeting (2012)

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