Synthesis and biological evaluation of certain alkenyldiarylmethanes as anti-HIV-1 agents which act as non-nucleoside reverse transcriptase inhibitors.
Several novel alkenyldiarylmethane (ADAM) non-nucleoside HIV-1 reverse transcriptase inhibitors were synthesized. The most potent of these proved to be 3',3"-dibromo-4',4"-dimethoxy-5'5"-bis(methoxycarbonyl)-1,1-diphenyl-1-+ ++heptene (8) ADAM 8 inhibited the cytopathic effect of HIV-1 in CEM cell culture with an EC50 value of 7.1 microM and was active against an array of laboratory strains of HIV-1 in CEM-SS and MT-4 cells, but was inactive as an inhibitor of HIV-2. In common with the other known non-nucleoside reverse transcriptase inhibitors, ADAM 8 was an effective inhibitor of HIV-1 reverse transcriptase (IC50 1 microM) with poly(rC).oligo(dG), but not with poly(rA).oligo(dT), as the template/primer. ADAM 8 was inactive against HIV-1 reverse transcriptases containing non-nucleoside reverse transcriptase inhibitor resistance mutations at residues 101, 106, 108, 139, 181, 188, and 236, while it remained active against enzymes with mutations at residues 74, 98, 100, 103, and at 103/181. An AZT-resistant virus having four mutations in reverse transcriptase was more sensitive to inhibition by ADAM 8 than the wild-type HIV-1. In addition, ADAM 8 displayed synergistic activity with AZT, but lacked synergy with ddI. ADAM 8 or a structurally related analog may therefore be useful as an antiviral agent in combination with AZT or with other NNRTIs that are made ineffective by mutations at residues which do not confer resistance to ADAM 8.
Cushman
M
M
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907, USA.
Golebiewski
W M
WM
Graham
L
L
Turpin
J A
JA
Rice
W G
WG
Fliakas-Boltz
V
V
Buckheit
R W
RW
D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001312:Aurintricarboxylic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D001565:Benzoates / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D002478:Cells, Cultured; D016049:Didanosine / Q000494:pharmacology; D004352:Drug Resistance, Microbial; D016655:HIV Core Protein p24 / Q000032:analysis; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008969:Molecular Sequence Data; D015394:Molecular Structure; D016297:Mutagenesis, Site-Directed; D012194:RNA-Directed DNA Polymerase / Q000378:metabolism*; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology
C100922:3',3''-dibromo-4',4''-dimethoxy-5',5''-bis(methoxycarbonyl)-1,1-diphenyl-1-heptene; D000998:Antiviral Agents; D001565:Benzoates; D001713:Biphenyl Compounds; D016655:HIV Core Protein p24; D018894:Reverse Transcriptase Inhibitors; C083060:cosalane; D001312:Aurintricarboxylic Acid; D054303:HIV Reverse Transcriptase; D012194:RNA-Directed DNA Polymerase; D016049:Didanosine