title: Activity of substituted thiophene sulfonamides against malarial and mammalian cyclin dependent protein kinases.
abstract: 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 IC(50) 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.
authors.affiliation: Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
authors.forename: Diana
authors.initials: D
authors.lastname: Caridha
authors.forename: April K
authors.initials: AK
authors.lastname: Kathcart
authors.forename: Dayadevi
authors.initials: D
authors.lastname: Jirage
authors.forename: Norman C
authors.initials: NC
authors.lastname: Waters
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008264:Macrophages / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects; D051381:Rats; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000962:Antimalarials; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D013449:Sulfonamides; D013876:Thiophenes; D018844:Cyclin-Dependent Kinases