Benzoylbenzimidazole-based selective inhibitors targeting Cryptosporidium parvum and Toxoplasma gondii calcium-dependent protein kinase-1

Calcium-dependent protein kinase-1 (CDPK1) from Cryptosporidium parvum (CpCDPK1) and Toxoplasma gondii (TgCDPK1) have become attractive targets for discovering selective inhibitors to combat infections caused by these protozoa. We used structure-based design to improve a series of benzoylbenzimidazo...

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Bibliographic Details
Published in:	Bioorganic & medicinal chemistry letters Vol. 22; no. 16; pp. 5264 - 5267
Main Authors:	Zhang, Zhongsheng, Ojo, Kayode K., Johnson, Steven M., Larson, Eric T., He, Penqing, Geiger, Jennifer A., Castellanos-Gonzalez, Alejandro, White, A. Clinton, Parsons, Marilyn, Merritt, Ethan A., Maly, Dustin J., Verlinde, Christophe L.M.J., Van Voorhis, Wesley C., Fan, Erkang
Format:	Journal Article
Language:	English
Published:	Amsterdam Elsevier Ltd 15-08-2012 Elsevier
Subjects:	Benzimidazoles - chemical synthesis Benzimidazoles - chemistry Benzimidazoles - metabolism Biological and medical sciences Calcium-dependent protein kinase-1 Cryptosporidium parvum Cryptosporidium parvum - enzymology Drug Design Enzyme inhibitor Humans Medical sciences Pharmacology. Drug treatments phosphotransferases (kinases) Protein Binding Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - metabolism Protein Kinases - chemistry Protein Kinases - metabolism Proto-Oncogene Proteins c-abl - antagonists & inhibitors Proto-Oncogene Proteins c-abl - metabolism Protozoan Proteins - antagonists & inhibitors Protozoan Proteins - metabolism Selectivity Solubility src-Family Kinases - antagonists & inhibitors src-Family Kinases - metabolism Structure-Activity Relationship Toxoplasma - enzymology Toxoplasma gondii Enzyme inhibitor Selectivity Toxoplasma gondii Cryptosporidium parvum Calcium-dependent protein kinase-1 Protozoa Apicomplexa Calcium Targeting Enzyme Transferases Non-specific serine/threonine protein kinase Inorganic element Signal transduction Target
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Summary:	Calcium-dependent protein kinase-1 (CDPK1) from Cryptosporidium parvum (CpCDPK1) and Toxoplasma gondii (TgCDPK1) have become attractive targets for discovering selective inhibitors to combat infections caused by these protozoa. We used structure-based design to improve a series of benzoylbenzimidazole-based compounds in terms of solubility, selectivity, and potency against CpCDPK1 and TgCDPK1. The best inhibitors show inhibitory potencies below 50nM and selectivity well above 200-fold over two human kinases with small gatekeeper residues.
Bibliography:	http://dx.doi.org/10.1016/j.bmcl.2012.06.050 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2012.06.050