4-benzyl- and 4-benzoyl-3-dimethylaminopyridin-2(1H)-ones, a new family of potent anti-HIV agents: optimization and in vitro evaluation against clinically important HIV mutant strains.
The 4-benzyl and 4-benzoyl-3-dimethylaminopyridinones 13 and 14 are representatives of a new class of highly potent non nucleoside type inhibitors of HIV-1 reverse transcriptase. To conduct SAR studies on these two lead compounds, 102 new analogues were prepared. Thirty-three compounds displayed nanomolar range activity in vitro against wild-type HIV-1, and among these, 18 were active against the 103N, Y181C, and Y188L mutant strains with IC50 values inferior to 1 microM. Evaluation of this group of analogues against an additional eight single [100I, 101E, 106A, 138K, 179E, 190A, 190S, 227C] and four double HIV mutant strains [100I + 103N, 101E + 103N, 103N + 181C, and 227L + 106A], which are often present in HIV infected patients, permitted the selection of eight compounds, 17x, 18b, 18c, 18f, 18g, 27, 30, and 42, which are globally more active than the lead molecules 13/14, emivirine and the currently used NNRTI, nevirapine. Further comparison of the 3'-CN-substituted benzoylpyridinone compound 18c, and the corresponding 3'-acrylonitrile-substituted analogue 30, to efavirenz, the reference molecule in anti-HIV therapy today, revealed that the pyridinone analogues displayed a superior inhibition profile in the in vitro cellular assay system. These results form a solid basis for continued optimization of the pyridinone series.
UMR 176 CNRS-Institut Curie, Laboratoire de Pharmacochimie, Section de Recherche, Batiment 110, Centre Universitaire, 91405 Orsay, France.
Abdellah
A
Benjahad
Karine
K
Courté
Jérôme
J
Guillemont
Dominique
D
Mabire
Sophie
S
Coupa
Alain
A
Poncelet
Imre
I
Csoka
Koen
K
Andries
Rudi
R
Pauwels
Marie-Pierre
MP
de Béthune
Claude
C
Monneret
Emile
E
Bisagni
Chi Hung
CH
Nguyen
David S
DS
Grierson
D000480:Alkynes; D000631:Aminopyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001555:Benzene Derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001565:Benzoates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D048588:Benzoxazines; D002460:Cell Line; D003521:Cyclopropanes; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D019829:Nevirapine / Q000737:chemistry / Q000494:pharmacology; D010078:Oxazines / Q000737:chemistry / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014498:Uracil / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
D000480:Alkynes; D000631:Aminopyridines; D019380:Anti-HIV Agents; D001555:Benzene Derivatives; D001565:Benzoates; D048588:Benzoxazines; D003521:Cyclopropanes; D010078:Oxazines; D018894:Reverse Transcriptase Inhibitors; D014498:Uracil; D019829:Nevirapine; C098320:efavirenz; C083858:emivirine