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

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          Abstract

          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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          Malnutrition as an enteric infectious disease with long-term effects on child development.

          Richard Guerrant, Reinaldo B. Oriá, Sean R. Moore … (2008)
          Malnutrition is a major contributor to mortality and is increasingly recognized as a cause of potentially lifelong functional disability. Yet, a rate-limiting step in achieving normal nutrition may be impaired absorptive function due to multiple repeated enteric infections. This is especially problematic in children whose diets are marginal. In malnourished individuals, the infections are even more devastating. This review documents the evidence that intestinal infections lead to malnutrition and that malnutrition worsens intestinal infections. The clinical data presented here derive largely from long-term cohort studies that are supported by controlled animal studies. Also reviewed are the mechanisms by which enteric infections lead to undernutrition and by which malnutrition worsens enteric infections, with implications for potential novel interventions. Further intervention studies are needed to document the relevance of these mechanisms and, most importantly, to interrupt the vicious diarrhea-malnutrition cycle so children may develop their full potential.
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            The genome of Cryptosporidium hominis.

            Ping Xu, Giovanni Widmer, Yingping Wang … (2004)
            Cryptosporidium species cause acute gastroenteritis and diarrhoea worldwide. They are members of the Apicomplexa--protozoan pathogens that invade host cells by using a specialized apical complex and are usually transmitted by an invertebrate vector or intermediate host. In contrast to other Apicomplexans, Cryptosporidium is transmitted by ingestion of oocysts and completes its life cycle in a single host. No therapy is available, and control focuses on eliminating oocysts in water supplies. Two species, C. hominis and C. parvum, which differ in host range, genotype and pathogenicity, are most relevant to humans. C. hominis is restricted to humans, whereas C. parvum also infects other mammals. Here we describe the eight-chromosome approximately 9.2-million-base genome of C. hominis. The complement of C. hominis protein-coding genes shows a striking concordance with the requirements imposed by the environmental niches the parasite inhabits. Energy metabolism is largely from glycolysis. Both aerobic and anaerobic metabolisms are available, the former requiring an alternative electron transport system in a simplified mitochondrion. Biosynthesis capabilities are limited, explaining an extensive array of transporters. Evidence of an apicoplast is absent, but genes associated with apical complex organelles are present. C. hominis and C. parvum exhibit very similar gene complements, and phenotypic differences between these parasites must be due to subtle sequence divergence.
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              The infectivity of Cryptosporidium parvum in healthy volunteers.

              H Dupont, W Jakubowski, Jane C Sterling … (1995)
              Small numbers of Cryptosporidium parvum oocysts can contaminate even treated drinking water, and ingestion of oocysts can cause diarrheal disease in normal as well as immunocompromised hosts. Since the number of organisms necessary to cause infection in humans is unknown, we performed a study to determine the infective dose of the parasite in healthy adults. After providing informed consent, 29 healthy volunteers without evidence of previous C. parvum infection, as determined by the absence of anti-cryptosporidium-specific antibodies, were given a single dose of 30 to 1 million C. parvum oocysts obtained from a calf. They were then monitored for oocyst excretion and clinical illness for eight weeks. Household contacts were monitored for secondary spread. Of the 16 subjects who received an intended dose of 300 or more oocysts, 14 (88 percent) became infected. After a dose of 30 oocysts, one of five subjects (20 percent) became infected, whereas at a dose of 1000 or more oocysts, seven of seven became infected. The median infective dose, calculated by linear regression, was 132 oocysts. Of the 18 subjects who excreted oocysts after the challenge dose, 11 had enteric symptoms and 7 (39 percent) had clinical cryptosporidiosis, consisting of diarrhea plus at least one other enteric symptom. All recovered, and there were no secondary cases of diarrhea among household contacts. In healthy adults with no serologic evidence of past infection with C. parvum, a low dose of C. parvum oocysts is sufficient to cause infection.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Med Chem
                Journal ID (iso-abbrev): J. Med. Chem
                Journal ID (publisher-id): jm
                Journal ID (coden): jmcmar
                Title: Journal of Medicinal Chemistry
                Publisher: American Chemical Society
                ISSN (Print): 0022-2623
                ISSN (Electronic): 1520-4804
                Publication date PMC-release: 04 December 2015
                Publication date (Electronic): 04 December 2014
                Publication date (Print): 26 December 2014
                Volume: 57
                Issue: 24
                Pages: 10544-10550
                Affiliations
                [† ]Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston , Science and Research Building 2, Room 549A, Houston, Texas 77204, United States
                [2] ‡Departments of Biology and §Chemistry, Brandeis University , 415 South Street, Waltham, Massachusetts 02454, United States
                [∥ ]Center for Structural Genomics of Infectious Diseases, Computational Institute, University of Chicago , 5735 South Ellis Avenue, Chicago, Illinois 60637, United States
                [⊥ ]Structural Biology Center, Biosciences, Argonne National Laboratory , 9700 South Cass Avenue Argonne, Illinois 60439, United States
                Author notes
                [* ]Phone: 1-713-743-1274. E-mail: gdcuny@ 123456central.uh.edu .
                Article
                DOI: 10.1021/jm501527z
                PMC ID: 4281095
                PubMed ID: 25474504
                SO-VID: a6a076de-ff13-4b5a-9634-7a0498cbffe7
                Copyright © Copyright © 2014 American Chemical Society
                License:

                This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

                History
                Date received : 03 July 2014
                Funding
                National Institutes of Health, United States
                Categories
                Subject: Brief Article
                Custom metadata
                document-id-old-9 jm501527z
                document-id-new-14 jm-2014-01527z
                ccc-price

                ScienceOpen disciplines: Pharmaceutical chemistry
                Data availability:
                ScienceOpen disciplines: Pharmaceutical chemistry

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