Activity of substituted thiophene sulfonamides against malarial and mammalian cyclin dependent protein kinases

Cyclin dependent protein kinases (CDKs) are pursued as drug targets for several eukaryotic pathogens. In this study, we identified thiophene and benzene sulfonamides as potent inhibitors of Pfmrk, a Plasmodium falciparum CDK with sequence homology to human CDK7. Several of the compounds demonstrated inhibitor selectivity for CDK7 over CDK1, CDK2, and CDK6. The compounds are moderate antimalarial agents against drug resistant parasites and possess encouraging in vitro therapeutic indices as determined against human cell lines. One particular sub-class of compounds, bromohydrosulfonylacetamides, was specific for Pfmrk with IC50 values in the sub-micromolar range. These compounds represent the most potent Pfmrk inhibitors reported and provide support for further characterization and derivation as potential antimalarial agents.

Graphical abstractVarious substituted thiophene and benzyl sulfonamides were identified as inhibitors of the plasmodial CDK, Pfmrk. Bromohydrosulfonylacetamides were selective for Pfmrk over human CDKs.Figure optionsDownload full-size imageDownload as PowerPoint slide