Synthesis and structural analysis of copper(II) pyridine amide complexes as HIV-1 protease inhibitors

Abstract

In an effort to propose original non-peptide HIV-1 protease inhibitors by rational drug design, we have previously reported that the complex diaqua[bis(2-pyridylcarbonyl)amido]copper(II) nitrate dihydrate behaved as a competitive inhibitor of the enzyme (K_i = 480 ± 120 µM). Based on a modeled interaction of this complex with HIV-1 protease, we present here the synthesis and crystallographic structures of two pyridine amide copper(II) coordination complexes, optimized for their interaction with the enzyme active site. The complexes adopted a tetragonally elongated octahedral geometry in the crystal. In both cases, two ligands symmetrically coordinate copper(II) by aromatic nitrogen and amide oxygen atoms, forming an equatorial square plane which may orient the various substituents within the enzyme subsites. As the apical positions form long bonds of 2.423(2) and 2.464(2) Å with copper(II), a statistical analysis was carried out in the Cambridge Structural Database. It gave for 1103 copper(II) complexes a mean copper(II)–oxygen distance of 2.450 ± 0.005 Å in the axial positions, typical of ‘long’ Cu–O bonds in Jahn–Teller distorted complexes of copper(II). The two compounds showed good inhibition of the HIV-1 protease (IC₅₀ = 1.5 and 1.0 µM).