Theoretical study of molecular structure, pKa, lipophilicity, solubility, absorption, and polar surface area of some hypoglycemic agents

The methods of theoretical chemistry have been used to elucidate molecular properties of the hypoglycemic sulfonylureas and glinides (acetohexamide, tofazamide, tolbutamide, chlorpropamide, gliclazide, glimepiride, glipizide, glibenclamide, nateglinide, and repaglinide). The geometries and energies of these drugs have been computed using HF/6-31G(d) and Becke3LYP/6-31G(d) methods. The equilibrium structure of the sulfonylureas investigated in the isolated state is determined by the formation of suitable intramolecular hydrogen bonds within the sulfonamide moiety. This specific interaction gives rise to the unique overall shape of individual drug conformers. Values of these dihedral angles for individual drugs are different. Generally, the ab initio SCF and DFT optimized structures in the gas phase fit well one another. Water has a remarkable effect on the geometry of the drugs studied. The pKa values of sulfonylurea moiety are in the range of 5.2-6.2 and these drugs are characterized as weak organic acids. Repaglinide and nateglinide are oral blood glucose-lowering drugs of the glinide class containing acidic carboxylic group. The pKa values of this carboxylic acid moiety are in the range of 3.5-4.0. Computed partition coefficients (XLOGP2 method) for drugs studied varied between 1.8 and 5.9. Thus these compounds are described as lipophilic drugs. Although the sulfonylurea and glinidine derivatives studied are only slightly soluble in water, their computed solubilities from interval between 0.001 and 4 g/L are sufficient for fast adsorption.