We have employed high-throughput whole-organism screening to discover novel anti-parasitic chemotypes. For Plasmodium falciparum, we previously disclosed a more extensive screening campaign on a library of about 2 million compounds using a cell-based proliferation assay of Plasmodium falciparum. Five thousand of the reconfirmed hits have subsequently disclosed in a public malaria database. The purpose of this work was to optimize hits from this collection to preclinical candidates by employing systematic structure-activity analysis. We analyzed the public hitlist with the following criteria: 1) good potency � IC50s were less than one micromolar against wild type as well as drug resistant strain 2) good safety index - greater than 20 fold in a 6-cell line toxicity panel and 3) easy of synthesis and preferably, with multiple active hits within the scaffold. We used systematic cell-based medicinal chemistry optimization to arrive at a potent compound with good in vivo efficacy, physiochemical properties and in vivo pharmacokinetics in a series of imidazolopiperazines, starting with compound GNF-Pf-5069 from the EBI list. In addition to this work, we have used a similar cell-based approach to find novel compounds fort the related kinetoplastid parasites, including Leishmania, African Sleeping Sickness and Chagas disease. The key challenges to finding novel preclinical candidates from these large hit-lists will be discussed.

Cell-based optimization of novel antiparasitics

243rd National Meeting (2012)

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