title: 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.
abstract: 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.
authors.affiliation: Laboratoire de Pharmacochimie, Section de Recherche, UMR 176 CNRS-Institut Curie, Batiment 110, Centre Universitaire, 91405 Orsay, France.
authors.forename: Abdellah
authors.initials: A
authors.lastname: Benjahad
authors.forename: Martine
authors.initials: M
authors.lastname: Croisy
authors.forename: Claude
authors.initials: C
authors.lastname: Monneret
authors.forename: Emile
authors.initials: E
authors.lastname: Bisagni
authors.forename: Dominique
authors.initials: D
authors.lastname: Mabire
authors.forename: Sophie
authors.initials: S
authors.lastname: Coupa
authors.forename: Alain
authors.initials: A
authors.lastname: Poncelet
authors.forename: Imre
authors.initials: I
authors.lastname: Csoka
authors.forename: Jérôme
authors.initials: J
authors.lastname: Guillemont
authors.forename: Christophe
authors.initials: C
authors.lastname: Meyer
authors.forename: Koen
authors.initials: K
authors.lastname: Andries
authors.forename: Rudi
authors.initials: R
authors.lastname: Pauwels
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: de Béthune
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Himmel
authors.forename: Kalyan
authors.initials: K
authors.lastname: Das
authors.forename: Eddy
authors.initials: E
authors.lastname: Arnold
authors.forename: Chi Hung
authors.initials: CH
authors.lastname: Nguyen
authors.forename: David S
authors.initials: DS
authors.lastname: Grierson
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D054303:HIV Reverse Transcriptase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000302:isolation & purification; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D011485:Protein Binding; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; D011725:Pyridines; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase