Synthesis and antiviral activity of 4-benzyl pyridinone derivatives as potent and selective non-nucleoside human immunodeficiency virus type 1 reverse transcriptase inhibitors.
Several 4-benzyl analogues of 5-ethyl-6-methyl-4-(phenylthio)pyridin-2(1H)-ones were synthesized and evaluated for their anti-HIV-l activities. Key transformations include metalation at the 4-C-position of 5-ethyl-2-methoxy-6-methyl-3-pivaloylaminopyridine (5) and its coupling with benzyl bromide or benzaldehyde derivatives. Biological studies revealed that some of the new 4-benzylpyridinones show potent HIV-1 specific reverse transcriptase inhibitory properties. Compounds 14, 19, and 27, which inhibit the replication of HIV-1 in CEM-SS cells, with IC(50) values ranging from 0.2 to 6 nM are the most active compounds in this series. Biochemical studies showed that compound 27 strongly inhibited the activity of a recombinant HIV-1 RT. Moreover, the infectivity of isolated HIV-1 particles was severely decreased after exposure to compound 27. Although cross resistance is frequently observed between non-nucleoside reverse transcriptase inhibitors, compound 27 was capable of inhibiting a virus resistant to nevirapine with an IC(50) of 40 nM.
Dollé
V
V
UMR 176 CNRS-Institut Curie, Section de Recherche, Bitiment 110, 15 rue Georges Climenceau, 91405 Orsay, France.
Nguyen
C H
CH
Legraverend
M
M
Aubertin
A M
AM
Kirn
A
A
Andreola
M L
ML
Ventura
M
M
Tarrago-Litvak
L
L
Bisagni
E
E
D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D002478:Cells, Cultured; D004352:Drug Resistance, Microbial; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D011728:Pyridones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012194:RNA-Directed DNA Polymerase / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014771:Virion / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
C415572:3-dimethylamino-4-(3,5-dimethylbenzyl)-5-ethyl-6-methylpyridin-2(1H)-one; D019380:Anti-HIV Agents; D011728:Pyridones; D011994:Recombinant Proteins; D018894:Reverse Transcriptase Inhibitors; D012194:RNA-Directed DNA Polymerase