Quantum Mechanical Prediction of Dissociation Constants for Thiazol-2-imine Derivatives

[Image: see text] 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 pK(a) of the drug molecule and the membrane environment. In this study, with the aim of predicting the acetonitrile pK(a)’s (pK(a(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 pK(a(water)) and pK(a(MeCN)). Highly well-correlated pK(a) values 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 pK(a(MeCN)) values of eight thiazol-2-imine structures, which were previously synthesized by some of us, are proposed.