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

Bioorganic & Medicinal Chemistry Letters
Diana CaridhaNorman C Waters

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.

References

Mar 20, 2004·Science·Martin E M NobleLouise N Johnson
Feb 22, 2005·Combinatorial Chemistry & High Throughput Screening·Susan M KeenanNorman C Waters
Mar 14, 2007·Current Drug Targets·Fernanda CanduriWalter F de Azevedo
Dec 7, 2007·Trends in Pharmacological Sciences·Marcos MalumbresJames R Bischoff

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Citations

Oct 4, 2011·BMC Genomics·Jennifer D ArtzRaymond Hui
Apr 12, 2015·Biochimica Et Biophysica Acta·Andreas Masch, Conrad Kunick
Jan 3, 2012·Parasitology International·Kentaro KatoTatsuya Iwanaga
Jun 1, 2011·Pharmaceuticals·Brian T Grimberg, Rajeev K Mehlotra
Jun 17, 2011·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Hosam A SaadMosselhi A Mosselhi
Nov 12, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Chantalle MoolmanLesetja J Legoabe
Dec 19, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Romain MustièreNicolas Primas
Nov 14, 2020·Expert Opinion on Investigational Drugs·Hanzhi LiangHao Fang
Jul 16, 2014·The Journal of Organic Chemistry·Mnaza NoreenGary A Molander
May 18, 2018·Journal of Medicinal Chemistry·Diego González CabreraKelly Chibale

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