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Open Source Drug Discovery: Highly Potent Antimalarial Compounds Derived from the Tres Cantos Arylpyrroles

2016; American Chemical Society; Volume: 2; Issue: 10 Linguagem: Inglês

10.1021/acscentsci.6b00086

2374-7951

Alice Williamson, Paul M. Ylioja, Murray N. Robertson, Yevgeniya Antonova‐Koch, Vicky M. Avery, Jonathan B. Baell, Harikrishna Batchu, Sanjay Batra, Jeremy N. Burrows, Soumya Bhattacharyya, Félix Calderón, Susan A. Charman, Julie Clark, Benigno Crespo, Matin Dean, Stefan L. Debbert, Michael J. Delves, Adelaide S. M. Dennis, Frederik Deroose, Sandra Duffy, Sabine Fletcher, Guri Giaever, Irene Hallyburton, Francisco‐Javier Gamo, Marinella Gebbia, R. Kiplin Guy, Zoë Hungerford, Kiaran Kirk, María José Lafuente-Monasterio, Anna Lee, Stephan Meister, Corey Nislow, John P. Overington, George Papadatos, Luc Patiny, James S. Pham, Stuart A. Ralph, Andrea Ruecker, Eileen Ryan, Christopher Southan, Kumkum Srivastava, Chris Swain, Matthew J. Tarnowski, Patrick Thomson, Peter Turner, Iain M. Wallace, Timothy N. C. Wells, Karen L. White, Laura M. White, Paul Willis, Elizabeth A. Winzeler, Sergio Wittlin, Matthew H. Todd,

Synthesis and Catalytic Reactions

The development of new antimalarial compounds remains a pivotal part of the strategy for malaria elimination. Recent large-scale phenotypic screens have provided a wealth of potential starting points for hit-to-lead campaigns. One such public set is explored, employing an open source research mechanism in which all data and ideas were shared in real time, anyone was able to participate, and patents were not sought. One chemical subseries was found to exhibit oral activity but contained a labile ester that could not be replaced without loss of activity, and the original hit exhibited remarkable sensitivity to minor structural change. A second subseries displayed high potency, including activity within gametocyte and liver stage assays, but at the cost of low solubility. As an open source research project, unexplored avenues are clearly identified and may be explored further by the community; new findings may be cumulatively added to the present work.