Differential antiviral activity of two TIBO derivatives against the human immunodeficiency and murine leukemia viruses alone and in combination with other anti-HIV agents.
R82913 and R86183, two derivatives of tetrahydroimidazo[4,5,1-jk][1,4]-benzodiazepin-2(1H)-thione (TIBO), were found to potently and selectively inhibit the replication and cell killing effects of a panel of biologically diverse laboratory and clinical strains of HIV-1. The two compounds exhibited significant activity in all human cell lines tested, as well as in fresh human peripheral blood lymphocytes and macrophages. One of these two compounds (R82913) was found to significantly inhibit the replication of a murine retrovirus (Rauscher murine leukemia virus) in both UV-XC plaque formation and virus yield reduction assays. R86183, despite differing from R82913 only in the positioning of a single chlorine molecule, was not active against the murine retrovirus but was 10-fold more potent in inhibiting HIV-1 replication. Combination antiviral assays with other reverse transcriptase inhibitors, including AZT, ddC, and carbovir, yielded synergistic anti-HIV activity with both TIBO derivatives. Additive to slightly synergistic results were obtained in combinations with ddI and phosphonoformic acid whereas additive to antagonistic activity was detected in combination with dextran sulfate.
Buckheit
R W
RW
Virology Research Division, Southern Research Institute-Frederick Research Center, Maryland 21701.
Germany-Decker
J
J
Hollingshead
M G
MG
Allen
L B
LB
Shannon
W M
WM
Janssen
P A
PA
Chirigos
M A
MA
D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001569:Benzodiazepines / Q000008:administration & dosage / Q000494:pharmacology*; D002460:Cell Line; D016049:Didanosine / Q000008:administration & dosage; D004357:Drug Synergism; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D015498:HIV-2 / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D011925:Rauscher Virus / Q000187:drug effects* / Q000502:physiology; D018894:Reverse Transcriptase Inhibitors; D014779:Virus Replication / Q000187:drug effects; D015215:Zidovudine / Q000008:administration & dosage
D000998:Antiviral Agents; D007093:Imidazoles; C086147:R 86183; D018894:Reverse Transcriptase Inhibitors; D001569:Benzodiazepines; D015215:Zidovudine; C067413:R-82913; D054303:HIV Reverse Transcriptase; D016049:Didanosine