Potent and selective inhibition of HIV-1 replication in vitro by a novel series of TIBO derivatives.
In the search for compounds active against human immunodeficiency virus (HIV), we have found that members of a novel series of tetrahydro-imidazo[4,5,1-jk][1,4]-benzodiazepine-2(1H)-one and -thione (TIBO) derivatives inhibit the replication of HIV-1, the main aetiological agent of AIDS, but not of HIV-2, or of any other DNA or RNA viruses. In five cell systems, HIV-1 is inhibited by TIBO derivatives in nanomolar amounts, which are 10(4)-10(5) times lower than the cytotoxic concentration. The unprecedented specificity of these compounds may be due to an interaction with a reverse transcriptase-associated process. By contrast, AZT (3'-azido-2',3'-dideoxythymidine), which is used for the treatment of AIDS, and DDC (2',3'-dideoxycytidine) and DDI (2',3'-dideoxyinosine), whose clinical application is being assessed, inhibit both HIV-1 and HIV-2 at concentrations that, depending on the cell systems, are 2 to 4 orders of magnitude below their cytotoxic concentration. TIBO-derivatives are new chemicals unrelated to any other antiviral agents. We believe that they are the most specific and potent inhibitors of HIV-1 replication studied so far.
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
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R
Pauwels
K
K
Andries
J
J
Desmyter
D
D
Schols
M J
MJ
Kukla
H J
HJ
Breslin
A
A
Raeymaeckers
J
J
Van Gelder
R
R
Woestenborghs
J
J
Heykants
D000818:Animals; D000998:Antiviral Agents; D001569:Benzodiazepines / Q000138:chemical synthesis / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000382:microbiology; D002460:Cell Line; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D016049:Didanosine / Q000494:pharmacology; D004285:Dogs; D015497:HIV-1 / Q000502:physiology*; D015498:HIV-2 / Q000502:physiology; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D008214:Lymphocytes / Q000382:microbiology; D008968:Molecular Conformation; D015394:Molecular Structure; D018894:Reverse Transcriptase Inhibitors; D014779:Virus Replication / Q000187:drug effects*; D015215:Zidovudine / Q000494:pharmacology
D000998:Antiviral Agents; D007093:Imidazoles; D018894:Reverse Transcriptase Inhibitors; C062687:R 82150; D001569:Benzodiazepines; D015215:Zidovudine; D016049:Didanosine