As weak acids or bases, in solution, drug molecules are
in either
their ionized or nonionized states. A high degree of ionization is
essential for good water solubility of a drug molecule and is required
for drug–receptor interactions, whereas the nonionized form
improves a drug’s lipophilicity, allowing the ligand to cross
the cell membrane. The penetration of a drug ligand through cell membranes
is mainly governed by the pKaof the drug
molecule and the membrane environment. In this study, with the aim
of predicting the acetonitrile pKa’s
(pKa(MeCN)) of eight drug-like thiazol-2-imine
derivatives, we propose a very accurate and computationally affordable
protocol by using several quantum mechanical approaches. Benchmark
studies were conducted on a set of training molecules, which were
selected from the literature with known pKa(water)and pKa(MeCN). Highly well-correlated
pKavalues were obtained when the calculations
were performed with the isodesmic method at the M062X/6-31G** level
of theory in conjunction with SMD solvation model for nitrogen-containing
heterocycles. Finally, experimentally unknown pKa(MeCN)values of eight thiazol-2-imine structures, which were
previously synthesized by some of us, are proposed.