Synthesis and structural analysis of the copper(II) complexes of N2-(2-pyridylmethyl)-2-pyridinecarboxamide

Previous investigations of the potential of metal–organic compounds as inhibitors of human immunodeficiency virus type I protease (HIV-1 PR) showed that the copper(II) complex diaqua [bis(2-pyridylcarbonyl)amido] copper(II) nitrate dihydrate and the complex bis[ N 2-(2,3,6-trimethoxybenzyl)-4-2-pyridinecarboxamide] copper(II) behaved as inhibitors of HIV-1 PR. In a search for similar readily accessible ligands, we synthesised and studied the structural properties of N 2-(2-pyridylmethyl)-2-pyridinecarboxamide (L) copper(II) complexes. Three different crystal structures were obtained. Two were found to contain ligand L simultaneously in a tridentate and bidentate conformation [Cu(L tri L bi )]. The other contained two symmetry-related ligands, coordinated through the pyridine nitrogen and the amide oxygen atoms [Cu(L bi ) 2 ]. A search of the Cambridge Structural Database indicated that L tri resulting from nitrogen bound amide hydrogen metal substitution is favoured over chelation through the amide oxygen atom. In our case, we calculated that the conformation of L tri is 11 kcal/mol more favourable than that of L bi . ESI-MS experiments showed that the Cu(L bi ) 2 structure could not be observed in solution, while Cu(L tri L bi )-related complexes were indeed present. The lack of protease inhibition of the pyridine carboxamide copper(II) complexes was explained by the fact that the Cu(L bi L tri ) complex could not fit into the HIV-1 active site.