4-Benzyl and 4-benzoyl-3-dimethylaminopyridin-2(1H)-ones: in vitro evaluation of new C-3-amino-substituted and C-5,6-alkyl-substituted analogues against clinically important HIV mutant strains
| Autor: | Dominique Jean-Pierre Mabire, Koen Andries, Chi Hung Nguyen, Alain Philippe Poncelet, Martine Croisy, Daniel M. Himmel, Christophe Meyer, Claude Monneret, Eddy Arnold, R Pauwels, Marie-Pierre de Béthune, Sophie Coupa, Kalyan Das, David Grierson, Jerome Emile Georges Guillemont, Abdellah Benjahad, Csoka Imre Christian Francis, Emile Bisagni |
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| Rok vydání: | 2005 |
| Předmět: |
Models
Molecular Molecular model Stereochemistry Anti-HIV Agents Pyridines Substituent Ether Crystallography X-Ray chemistry.chemical_compound Structure-Activity Relationship Drug Discovery Structure–activity relationship Combinatorial Chemistry Techniques Hydroxymethyl Alkyl chemistry.chemical_classification Binding Sites HIV Reverse Transcriptase chemistry Mutation Lactam HIV-1 Mutagenesis Site-Directed Molecular Medicine Reverse Transcriptase Inhibitors Methyl group Protein Binding |
| Zdroj: | Journal of medicinal chemistry |
| ISSN: | 0022-2623 |
| Popis: | In a program to optimize the anti-HIV activity of the 4-benzyl and 4-benzoyl-3-dimethylaminopyridinones 9 and 10, lead compounds in a new class of highly potent non-nucleoside type inhibitors of HIV-1 reverse transcriptase, modification of the alkyl substitutents at the C-5 and C-6 positions on the pyridinone ring and of the substitutents on the C-3 amino group has been studied. Of the 17 new 5/6-modified analogues prepared, compounds 31b and 32b substituted at C-5 by an extended nonpolar chain containing an ether function and a C-6 methyl group and compound 35 bearing a C-5 ethyl/C-6 hydroxymethyl substituent pattern were selected on the basis of their in vitro activity against wild-type HIV and the three principle mutant strains, K103N, Y181C, and Y188L. When tested further, it was shown that these molecules, and in particular compound 35, are globally more active than 9, 10, and efavirenz against an additional eight single [L100I, K101E, V106A, E138K, V179E, G190A/S, and F227C] and four double HIV mutant strains [L100I + K103N, K101E + K103N, K103N + Y181C, and F227L + V106A], which are clinically relevant. Concerning modulation of the N-3 substituent, 36 new analogues were prepared. Of these, the N-methyl-N-(2-methoxyethyl)-substituted compounds 40, 42, and 62, as well as the doubly modified compounds 77a and 77b, were selected from the initial screen and were subsequently shown to be active at sub-micromolar concentrations (IC(50)'s) against all the other mutant strains except K103N + Y181C and F227L + V106A. Two possible, but distinct, modes of binding of these analogues in RT were suggested from molecular modeling studies. The preferred mode of binding for compound 62, corresponding to the predicted "orientation 1", was revealed in the X-ray crystal structure of the compound 62-RT complex. |
| Databáze: | OpenAIRE |
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