High-throughput screening of a set of 8,000 molecules from the Broad Institute diversity-oriented synthesis compound collection in a P. falciparum live/dead assay led to the identification of 560 novel compounds inhibiting parasite growth by over 90% at 5 �M. Upon resynthesis of a small subset of these hits from different scaffold classes, a lead series was chosen for further optimization to improve potency and physicochemical properties. Through analysis of the primary screening data along with analog synthesis, significant structure activity relationships (SAR) along with stereochemical-structure activity relationships were realized. Initial SAR of the lead series was investigated and optimization studies led to compounds that fully inhibit the growth of P. falciparum at < 5 nM with water solubilites from 100 to 300 �M. The SAR of major scaffold changes including macrocyclic ring contraction and the removal of stereocenters will be described along with results from in vivo testing.

Discovery and optimization of novel antimalarials via diversity-oriented synthesis

245th National Meeting (2013)

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