Abstract
Pyrimidines are key components in the genetic code of living organisms and the pyrimidine scaffold is also found in many bioactive and medicinal compounds. The acidities of these compounds, as represented by their pKas, are of special interest since they determine the species that will prevail under different pH conditions. Here, a quantum chemical quantitative structure–activity relationship (QSAR) approach was employed to estimate these acidities. Density-functional theory calculations at the B3LYP/6-31+G(d,p) level and the SM8 aqueous solvent model were employed, and the energy difference ∆EH2O between the parent compound and its dissociation product was used as a variation parameter. Excellent estimates for both the cation → neutral (pKa1, R2 = 0.965) and neutral → anion (pKa2, R2 = 0.962) dissociations were obtained. A commercial package from Advanced Chemical Design also yielded excellent results for these acidities.
Highlights
Pyrimidines play a central role in the terrestrial genetic code and the pyrimidine framework is found in many bioactive compounds and medicines
Among the most important and interesting properties of the pyrimidines are their acidities, as represented by their pKa values, which determine the forms of the compounds that will prevail in solution under different pH conditions
In the present work we develop estimates for the acidities of pyrimidines and related compounds
Summary
Pyrimidines play a central role in the terrestrial genetic code and the pyrimidine framework is found in many bioactive compounds and medicines. There has been a long-standing interest in estimating the pKas of chemical compounds using theoretical approaches [1,2]. This interest continues, as demonstrated by the broad range of methods employed in recent pKa studies [3,4,5,6,7,8,9,10]. In an earlier study by our group [11], we presented computational estimates of the pKas of the biologically related purines and indoles. In the present work we develop estimates for the acidities of pyrimidines and related compounds
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