A MOLECULAR-ORBITAL STUDY OF AMILORIDE

Molecular orbital calculations with geometry optimization in the 3-21G(*) basis set were carried out for the acylimino (A, 1a) and the isoimino (E, 1b) tautomers of the free base form of amiloride, and for the protonated form (F, 1c) of amiloride. The results showed the E1 tautomer to be 16.8 kcal/mol higher in energy than the A conformer of lowest energy, A1. The protonation energy of the A1 species was found to be 269.4 kcal/mol. Similar results were obtained using the AM1 method. These results are in agreement with the NMR results of Smith et al. which show the A and F species to be predominant in solution. The 3-21G(*) rotational barrier for the acylimino tautomer was found to be 19.0 kcal/mol, with the A4 conformer 2.50 kcal/mol higher in energy than the A1.