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.
Highlights
Malaria remains one of the world’s most deadly diseases
This approach was found to be superior to an alternative method involving initial synthesis of the unfunctionalized N-arylpyrrole, followed by conversion to the corresponding aldehyde with a Vilsmeier−Haack reaction (a procedure that was improved through a community suggestion (Figure S3)67) and oxidation to a carboxylic acid, because the pyrrole aldehyde was found to be remarkably resilient to a range of oxidants. (An alternative route using a Friedel−Crafts acylation between the unsubstituted pyrrole and ethyl chloroformate, suggested in an e-mail from the community, gave only starting material in two attempts.)
To confirm the promise of the two starting points OSM-S-5 and -6, they were evaluated against 3D7 and K1 strains of Plasmodium falciparum in a whole cell assay and against HEK-293 cells as a cytotoxicity marker (Table SB1, Biological Protocols; tables with the prefix “SB” may be found in the Supporting Information)
Summary
Malaria remains one of the world’s most deadly diseases. There were an estimated 214 million cases of malaria in 2015, including around 438,000 deaths of which the majority, tragically, were young children.[1]. In silico pharmacophore modeling has to date proven ineffective at high-confidence analogue prediction, but this remains an open challenge[99] to which others may contribute given the data set available.[68,69] Some preliminary results suggesting a common feature map for the arylpyrrole and NN subseries were of particular interest and could be explored with the more substantial bioactivity data available Along these lines, an automated bioisosteric replacement analysis[100] was performed for the NN series (Text S8, Data Set S19) focusing on replacement of the pyrrole phenyl substituent, and output suggestions were generated for potent compound OSM-S-35 (Figures S27−S30); these may be explored in the future. In each case there was no significant effect on [Na+]i, consistent with PfATP4 not being the relevant biological target of this compound class (Data Set S37; Figure S38)
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