Synthesis, in Vitro Evaluation and Cocrystal Structure of 4-Oxo-[1]benzopyrano[4,3-c]pyrazole Cryptosporidium parvum Inosine 5′-Monophosphate Dehydrogenase (CpIMPDH) Inhibitors

[Image: see text] Cryptosporidium inosine 5′-monophosphate dehydrogenase (CpIMPDH) has emerged as a therapeutic target for treating Cryptosporidium parasites because it catalyzes a critical step in guanine nucleotide biosynthesis. A 4-oxo-[1]benzopyrano[4,3-c]pyrazole derivative was identified as a...

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Detalles Bibliográficos
Autores principales: Sun, Zhuming, Khan, Jihan, Makowska-Grzyska, Magdalena, Zhang, Minjia, Cho, Joon Hyung, Suebsuwong, Chalada, Vo, Pascal, Gollapalli, Deviprasad R., Kim, Youngchang, Joachimiak, Andrzej, Hedstrom, Lizbeth, Cuny, Gregory D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2014
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4281095/
https://www.ncbi.nlm.nih.gov/pubmed/25474504
http://dx.doi.org/10.1021/jm501527z
Descripción
Sumario:[Image: see text] Cryptosporidium inosine 5′-monophosphate dehydrogenase (CpIMPDH) has emerged as a therapeutic target for treating Cryptosporidium parasites because it catalyzes a critical step in guanine nucleotide biosynthesis. A 4-oxo-[1]benzopyrano[4,3-c]pyrazole derivative was identified as a moderately potent (IC(50) = 1.5 μM) inhibitor of CpIMPDH. We report a SAR study for this compound series resulting in 8k (IC(50) = 20 ± 4 nM). In addition, an X-ray crystal structure of CpIMPDH·IMP·8k is also presented.

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