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Synthesis and Pharmacological Screening of Pyridopyrimidines as Effective Anti-Diarrheal Agents through the Suppression of Cyclic Nucleotide Accumulation. | LitMetric

AI Article Synopsis

  • - Increased levels of cyclic nucleotides (cGMP and cAMP) in enterocytes lead to secretory diarrhea due to enhanced ion and fluid secretion.
  • - A series of novel pyridopyrimidines were synthesized and tested; they didn't affect basal cyclic nucleotide levels or cell viability, but one compound significantly reduced cGMP and cAMP accumulation in specific cell types.
  • - The active compound was effective in a rabbit diarrhea model, showing preservation of intestinal health with minimal inflammation and stability against oxidation in lab tests.

Article Abstract

The increased levels of cyclic nucleotides (cGMP and cAMP) in enterocytes trigger intracellular mechanisms of ion and fluid secretion into the lumen, causing secretory diarrhea. Twelve novel pyridopyrimidines derived from 5-(3,5-bistrifluoromethylphenyl)-1,3-dimethyl-5,11-dihydro-1H-indeno[2,1 : 5,6]pyrido[2,3-d]pyrimidine-2,4,6-trione (FPIPP) were synthesized and evaluated on intracellular cyclic nucleotide accumulation. All compounds had no effect on either cyclic nucleotide basal levels or on pre-contracted aortic rings. The metabolic activity and viability in T84 cells, assessed by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) and the LDH (lactate dehydrogenase) assays, respectively, were not affected by incubation with the compounds (50 μM). Compound almost abolished cGMP accumulation (94 % inhibition) induced by STa toxin in T834 cells and significantly reduced (69 %) forskolin-induced cAMP accumulation in Jurkat cells. Compound was active in an in vivo model for diarrhea in rabbits. These results prompted us to perform a microscopic histopathological analysis of intestinal tissues, showing that only compound preserves the intestine without significant pathological changes and with a decreased inflammatory pattern in comparison to FPIPP. In vitro stability test revealed that compound is resistant to oxidation promoted by atmospheric oxygen.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454219PMC
http://dx.doi.org/10.1002/open.201900060DOI Listing

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