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Synthesis and evaluation of antidiarrheal activity and bioavailability of new pyridopyrimidines analogs

Grant number: 13/15525-1
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): July 01, 2014
Effective date (End): December 31, 2017
Field of knowledge:Biological Sciences - Pharmacology - General Pharmacology
Cooperation agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
Principal Investigator:Gilberto de Nucci
Grantee:Tiago Zaminelli
Home Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil


Responsible for thousands of deaths each year, secretory diarrhea is the second leading cause of infant mortality in developing countries, being mainly caused by infection by enterotoxigenic Escherichia coli (ETEC). These strains synthesize several toxins such as heat stable toxin "A" (STa) that interact with the guanylyl cyclase type C receptor (GC- C) localized in the intestinal epithelium. These interactions induces an increase in intracellular cyclic guanosine monophosphate (cGMP) that are responsible for inducing an increase in the efflux of chloride and fluid accumulation in the intestinal lumen. Recently it has been described a novel class of pyridopyrimidine derivatives (BPIPP and analogs) with a suppressive potential against the accumulation of cyclic nucleotides stimulated by toxins STa (ETEC), Bacillus anthracis and Vibrio cholerae. Although BPIPP and its analogs are considered promising compounds for the treatment of secretory diarrhea, a possible clinical application of these depends on further studies leading to improved solubility profile, in addition to bioavailability and in vivo efficacy evaluation. Thus, the aim of this work is to synthesize new compounds derivatives from pyridopyrimidine that exhibit inhibitory activity on the synthesis of cyclic nucleotides stimulated by STa toxin, as well as better pharmacokinetic profile compared to the previously compounds. Furthermore, we propose to evaluate the antidiarrheal activity (in vitro and in vivo) and the bioavailability of these unprecedented and promising molecules, candidates for the treatment of secretory diarrhea of infectious, autoimmune and drug etiology. (AU)

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
ZAMINELLI, TIAGO; MAGLI, ELISA; FRECENTESE, FRANCESCO; LESCANO, CAROLINE H.; CAMPOS, RAFAEL; SACCONE, IRENE; CORVINO, ANGELA; DI VAIO, PAOLA; GIORDANO, FLAVIA; LUCIANO, PAOLO; FIORINO, FERDINANDO; PERISSUTTI, ELISA; SANTAGADA, VINCENZO; SEVERINO, BEATRICE; CALIENDO, GIUSEPPE; DE NUCCI, GILBERTO. Synthesis and Pharmacological Screening of Pyridopyrimidines as Effective Anti-Diarrheal Agents through the Suppression of Cyclic Nucleotide Accumulation. CHEMISTRYOPEN, v. 8, n. 4, p. 464-475, APR 2019. Web of Science Citations: 0.
Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
ZAMINELLI, Tiago. . 2018. Doctoral Thesis - Universidade Estadual de Campinas, Faculdade de Ci?ncias M?dicas.

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