Open source drug discovery : highly potent antimalarial compounds derived from the tres cantos arylpyrroles

Williamson, Alice E and Ylioja, Paul M and Robertson, Murray N and Antonova-Koch, Yevgeniya and Avery, Vicky and Baell, Jonathan B and Batchu, Harikrishna and Batra, Sanjay and Burrows, Jeremy N and Bhattacharyya, Soumya and Calderon, Felix and Charman, Susan A and Clark, Julie and Crespo, Benigno and Dean, Matin and Debbert, Stefan L and Delves, Michael and Dennis, Adelaide S M and Deroose, Frederik and Duffy, Sandra and Fletcher, Sabine and Giaever, Guri and Hallyburton, Irene and Gamo, Francisco-Javier and Gebbia, Marinella and Guy, R Kiplin and Hungerford, Zoe and Kirk, Kiaran and Lafuente-Monasterio, Maria J and Lee, Anna and Meister, Stephan and Nislow, Corey and Overington, John P and Papadatos, George and Patiny, Luc and Pham, James and Ralph, Stuart A and Ruecker, Andrea and Ryan, Eileen and Southan, Christopher and Srivastava, Kumkum and Swain, Chris and Tarnowski, Matthew J and Thomson, Patrick and Turner, Peter and Wallace, Iain M and Wells, Timothy N C and White, Karen and White, Laura and Willis, Paul and Winzeler, Elizabeth A and Wittlin, Sergio and Todd, Matthew H (2016) Open source drug discovery : highly potent antimalarial compounds derived from the tres cantos arylpyrroles. ACS central science, 2 (10). pp. 687-701. ISSN 2374-7951

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    Abstract

    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.