Metal-organic compounds: a new approach for drug discovery. N1-(4-methyl-2-pyridyl)-2,3,6-trimethoxybenzamide copper(II) complex as an inhibitor of human immunodeficiency virus 1 protease.
The use of metal-organic complexes is a potentially fruitful approach for the development of novel enzyme inhibitors. They hold the attractive promise of forming stronger attachments with the target by combining the co-ordination ability of metals with the unique stereoelectronic properties of the ligand. We demonstrated that this approach can be successfully used to inhibit the protease of the human immunodeficiency virus (type 1). Several ligands bearing substituents designed to interact with the catalytic site of the enzyme when complexed to Cu(2+) were synthesised. The inhibition pattern of the resulting copper(II) complexes was analysed. We showed that the copper(II) complex of N1-(4-methyl-2-pyridyl)-2,3,6-trimethoxybenzamide (C1) interacts with the active site of the enzyme leading to competitive inhibition. On the other hand, N2-pyridine-amide ligands and oxazinane carboxamide ligand were found to be poor chelators of the cupric ion under the enzymatic assay conditions. In these cases, the observed inhibition was attributed to released cupric ions which react with cysteine residues on the surface of the protease. While unchelated metal cations are not likely to be useful agents, metal chelates such as C1 should be considered as promising lead compounds for the development of targeted drugs.
Lebon
Florence
F
Facultés Universitaires Notre-Dame de la Paix, Laboratoire de Chimie Moléculaire Structurale, 61 rue de Bruxelles, 5000 Namur, Belgium.
Boggetto
Nicole
N
Ledecq
Marie
M
Durant
François
F
Benatallah
Zohra
Z
Sicsic
Sames
S
Lapouyade
René
R
Kahn
Olivier
O
Mouithys-Mickalad
Ange
A
Deby-Dupont
Ginette
G
Reboud-Ravaux
Michèle
M
D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D004578:Electron Spin Resonance Spectroscopy; D016333:HIV Protease / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D001549:Benzamides; D017320:HIV Protease Inhibitors; C459399:N1-(4-methyl-2-pyridyl)-2,3,6-trimethoxybenzamide copper(II) complex; D009942:Organometallic Compounds; D011725:Pyridines; D016333:HIV Protease