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

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.