We have previously developed a new family of organometallic complexes targeting the HIV-1 protease, an enzyme that is essential for viral maturation. Among these, two Cu2+ complexes C1 and C2 were synthesized from flexible ligands L1, N1-(4-methyl-2-pyridyl)-2,3,6-trimethoxybenzamide and L2, N2-(2-methoxybenzyl)-2-quinolinecarboxamide, respectively. These ligands, designed to fit the protease active site, were shown to form 2:1 complexes with Cu2+. To compare the relative stability of C1 and C2 and to study the energetic and structural aspects of such large Cu2+ complexes, we have extended the polarizable molecular mechanics procedure SIBFA to treat this cation. This was done by carrying out parallel ab initio (HF, MP2) as well as DFT computations. A first validation step was done on monoligated complexes, in which the SIBFA energy components were shown to correctly match their ab initio counterparts from an energy-decomposition procedure. Subsequent tests on polyligated Cu2+ complexes with neutral and anionic ligands showed the procedure to reproduce the results from MP2 and DFT computations with good accuracy (relative error <3%). We have next extended the calculations to compare the C1 and C2 complexes. Energy balances including continuum solvation effects indicate a greater stability of the C1 complex, in agreement with experimental results. The effects of the methoxyphenyl substituents on the C1 complex stability were further investigated and compared to their concomitant influences on the ab initio-computed molecular electrostatic potential.

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[N2-(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 N2-(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(LtriLbi)]. The other contained two symmetry-related ligands, coordinated through the pyridine nitrogen and the amide oxygen atoms [Cu(Lbi)2]. A search of the Cambridge Structural Database indicated that Ltri 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 Ltri is 11 kcal/mol more favourable than that of Lbi. ESI-MS experiments showed that the Cu(Lbi)2 structure could not be observed in solution, while Cu(LtriLbi)-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(LbiLtri) complex could not fit into the HIV-1 active site.

Recently, western countries have recorded a decrease in the death rate imputed to AIDS. This success has been largely attributed to the presence on the market of chemotherapies that inhibit the infectivity of the predominant causative agent, the HIV-1 virus, by targeting essential viral enzymes. One of these is the protease (HIV-1 PR) whose activity is a prerequisite for viral replication. Two main sites have been identified as poten-tial targets for the inhibition of HIV-1 PR, the active site and the interface, the latter being largely responsible for the stabilization of the enzyme dimeric structure. The compounds that have reached clinical application so far target the active site of HIV-1 PR. These molecules act as transition state analogues and result from modifications of the peptidic scaffold into peptidomimetics. In order to improve their bioavailability, systematic biological screening and de novo design have been used to suggest new non-peptide inhibitors combining both antiviral potency and favorable pharmacokinetic properties. In parallel, compounds targeting other potential sites of inhibition have been tested. Peptides and peptidomimetics based on the terminal sequence of the enzyme, a site which is proposed to be less susceptible to mutations, have been shown to lead to HIV-1 PR inactivation. Cupric ion was described to bind a sequence on the protease surface, which includes cysteine and histidine residues, leading to the inhibition of the enzyme. In the future, these non-active site inhibitors could provide an alternative in anti-HIV drug combination strategies.

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-1 = 480 +/- 120 mu M). 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) Angstrom with copper(II), a statistical analysis was carried out in the Cambridge Structural Database. It gave for 1103 copper(rr) complexes a mean copper(lr)-oxygen distance of 2.450 +/- 0.005 Angstrom 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 mu M).