Theoretical study of structure, pKa, lipophilicity, solubility, absorption, and polar surface area of some centrally acting antihypertensives

The methods of theoretical chemistry have been used to elucidate the molecular properties of the substituted imidazoline and oxazoline structures, a class of potent agonists and antagonists of imidazoline receptors. The geometries of various tautomers and isomers of 2-[2,6-dichlorophenylimino] imidazolidine (clonidine), 1-(N-dicyclopropylmethyl)amino-2-oxazoline (rilmenidine), 4-chloro-N-(4,5-dihydro-1H-imidazol-2yl)-6-methoxy-2-methyl-5- pyrimidinamine (moxonidine), N-(dicyclopropylmethyl)-4,5-dihydro-1H-pyrrol-2- amine (aminopyrroline), N-dicyclopropylmethyl-4,5-dihydrothiazol-2-amine (aminothiazoline), 4,5-dihydro-2-(2-methoxyphenyl)-1H-imidazole (compound_6), 4,5-dihydro-2-(3-methylthiophen-2-yl)-1H-imidazole (compound_7), N-(2-chloro-4-iodophenyl)-4,5-dihydro-5-methyl-3H-pyrrol-2-amine (LNP_911), N-amidino-3,5-diamino-6-chloropyrazine-carboxamide (amiloride), 2-(1,4-benzodioxan-2-yl)-2-imidazoline (idazoxan), (±)-2-(2-ethyl-2,3- dihydro-2-benzofuranyl)-2-imidazoline (efaroxan), (4-aminobutyl)guaninine (agmatine), and 1-methyl-9H-pyrido[3,4-b]indole (harmane) have been studied using Becke3LYP/6-31+G(d,p) and BP86/TZ2P DFT methods. The optimized geometries indicate that these molecules show a distinctly nonplanar configuration of the imidazoline and oxazoline moieties. In the gas-phase, rilmenidine and aminothiazoline exist in two forms (amino and imino), the amino tautomers being more stable by about 6 kJ/mol. The calculations showed, in agreement with experiments, that clonidine, moxonidine, and LNP_911 exist in a more stable imino tautomer. The tautomer containing the amino group is by about 30 kJ/mol less stable. Computations that include the effect of solvation indicated that also in water the relative stability order of individual tautomers (amino and imino forms) is preserved. The computed pK