An expeditious access to 5-pyrimidinol derivatives from cyclic methylglyoxal diadducts, formation of argpyrimidines under physiological conditions and discovery of new CFTR inhibitors

In the study of previously reported modulators of CFTR chloride channels that are cyclic methylglyoxal (MG) diadducts (CMGD) to aromatic α-aminoazaheterocycles, we optimized a new expeditious one pot route for preparing in water novel aromatic polycyclic azaheterocycles and described 5-pyrimidinols antioxidants through the formation of 2-oxoaldehyde diadducts to aromatic α-aminoazaheterocycles, amidines, guanidines and thiourea. In regard to the importance as biomarkers of diabetic complications of the 5-pyrimidinols “argpyrimidines” formed in proteins from MG and arginine residues, we demonstrated that argpyrimidines are slowly formed under physiological conditions from CMGD to arginine derivatives according to the synthesis route described. Among the 5-pyrimidinol derivatives prepared, two polycyclic derivatives appeared to inhibit strongly the activity of CFTR channels in wt-CHO cells.

We describe an expeditious route for preparing azaheterocycles and 5-pyrimidinols antioxidants from methylglyoxal (MG), show that the biomarkers of diabetic complications “argpyrimidines” are formed from MG cycloadducts and identify inhibitors of CFTR.Figure optionsDownload as PowerPoint slideHighlights
► New synthesis of antioxidant 5-pyrimidinols and related new polycyclic derivatives.
► Quick and versatile one pot route in water from low cost commercial reagents.
► Identification of two strong CFTR inhibitors: treatment of diarrheas and cholera.
► Diabete: modification of proteins by methylglyoxal and formation of argpyrimidines.