Potent and Selective Inhibitors of CDPK1 from T. gondii and C. parvum Based on a 5‑Aminopyrazole-4-carboxamide Scaffold

• Published in: ACS medicinal chemistry letters Vol. 5; no. 1; pp. 40 - 44
• Main Authors: Zhang, Zhongsheng, Ojo, Kayode K, Vidadala, RamaSubbaRao, Huang, Wenlin, Geiger, Jennifer A, Scheele, Suzanne, Choi, Ryan, Reid, Molly C, Keyloun, Katelyn R, Rivas, Kasey, Kallur Siddaramaiah, Latha, Comess, Kenneth M, Robinson, Kenneth P, Merta, Philip J, Kifle, Lemma, Hol, Wim G. J, 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: WASHINGTON American Chemical Society 09.01.2014; Amer Chemical Soc
• Subjects: Chemistry, Medicinal; Letter; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; selectivity; Toxoplasma gondii; Cryptosporidium parvum; enzyme inhibitor; calcium-dependent protein kinase-1; MAP KINASE; BINDING; PROTEIN-KINASE 1; CHILDREN; Enzyme inhibitor; Selectivity; Calcium-dependent protein kinase-1
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/ml400315s

5-Aminopyrazole-4-carboxamide was used as an alternative scaffold to substitute for the pyrazolopyrimidine of a known “bumped kinase inhibitor” to create selective inhibitors of calcium-dependent protein kinase-1 from both Toxoplasma gondii and Cryptosporidium parvum. Compounds with low nanomolar inhibitory potencies against the target enzymes were obtained. The most selective inhibitors also exhibited submicromolar activities in T. gondii cell proliferation assays and were shown to be nontoxic to mammalian cells.