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

Author(s):Show less -

Zaminelli, Tiago ^[1] ; Magli, Elisa ^[2] ; Frecentese, Francesco ^[2] ; Lescano, Caroline H. ^[1] ; Campos, Rafael ^[1] ; Saccone, Irene ^[2] ; Corvino, Angela ^[2] ; Di Vaio, Paola ^[2] ; Giordano, Flavia ^[2] ; Luciano, Paolo ^[2] ; Fiorino, Ferdinando ^[2] ; Perissutti, Elisa ^[2] ; Santagada, Vincenzo ^[2] ; Severino, Beatrice ^[2] ; Caliendo, Giuseppe ^[2] ; De Nucci, Gilberto ^[1]

Affiliation

^[1] Ceara State Univ UECE, Super Inst Biomed Sci, Fortaleza, Ceara - Brazil

^[2] Univ Naples Federico II, Dept Pharm, Via D Montesano 49, I-80131 Naples - Italy

• Document type: Journal article
• Source: CHEMISTRYOPEN; v. 8, n. 4, p. 464-475, APR 2019.
• Web of Science Citations: 0

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 (50M). Compound VI 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 VI was active in an invivo model for diarrhea in rabbits. These results prompted us to perform a microscopic histopathological analysis of intestinal tissues, showing that only compound VI preserves the intestine without significant pathological changes and with a decreased inflammatory pattern in comparison to FPIPP. In vitro stability test revealed that compound VI is resistant to oxidation promoted by atmospheric oxygen. (AU)

• FAPESP's process: 13/15525-1 - Synthesis and evaluation of antidiarrheal activity and bioavailability of new pyridopyrimidines analogs
• Grantee: Tiago Zaminelli
• Support Opportunities: Scholarships in Brazil - Doctorate