Cryptosporidium are protozoan parasites causing diarrheal disease in both humans and animals.  Although infection is limiting in healthy adults, it can be life-threating in children and immune compromised individuals.  Also since the organisms can easily be introduced into the water supply, they present credible bioterrorism threats.  Currently, effective therapy is lacking.  Inspection of Cryptosporidium genomes revealed the enzyme inosine 5'-monophosphate dehydrogenase (IMPDH) catalyzes the rate-determining step in the only pathway to guanine nucleotides in both C. parvum and C. hominis. Moreover, the Cryptosporidium IMPDH gene was likely obtained by lateral gene transfer from bacteria.  Hence, CpIMPDH is highly divergent from its host counterparts making it a potentially viable molecular target for treating cryptosporidiosis. Compounds based on a benzopyrano-4(1H)-one derivative were identified as selective inhibitors of C. parvum IMPDH in a previous study. Herein we report the initial structure-activity relationship (SAR) for this compound series, which will guide additional optimization in order to obtain candidate compounds for evaluation in cell infectivity models and potentially in an in vivo disease model.

Benzopyrano-4(1H)-ones as Cryptosporidium Parvum inosine 5'-monophosphate fehydrogenase (CpIMPDH) inhibitors

247th National Meeting (2014)

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