New arylpyrido-diazepine and -thiodiazepine derivatives are potent and highly selective HIV-1 inhibitors targeted at the reverse transcriptase

Antiviral Res. 1996 May;30(2-3):109-24. doi: 10.1016/0166-3542(95)00906-x.


A series of pyridobenzothiodiazepindioxides such as the 11-ethyl-6,8,9-trimethyl-6,11-dihydro-pyrido[2,3-f] [2,1,5]benzothiodiazepine-5,5-dioxide and arylpiridodiazepines such as the 6,7-dihydro-7-methyl-12-ethyl-pyrido[2,3-b] pyrido(2',3'-4,5]furo[2,3-f][1,4]diazepin-6(12H)-thio and the 6,7-dihydro-7-methyl-12-ethyl-pyrido[2,3-b]pyrido- [2,3-4,5]thieno[2,3-f][1,4] diazepin-6(12H)-thione were found to inhibit human immunodeficiency virus type 1 [HIV-1(IIIB)] replication at a concentration of 0.003-0.04 microM without being cytotoxic at a 3,000- to 15,000-fold higher concentration. These compounds proved effective against a variety of HIV-1 strains, including those that are resistant to 3'-azido-3' deoxythymidine (AZT), but not against HIV-2, simian immunodeficiency virus or herpes simplex virus. An HIV-1 strain containing the 188 Tyr-->His mutation in the reverse transcriptase displayed severely reduced sensitivity to the compounds. The specificity of these compounds is due to an interaction with the reverse transcription process. The 6,7-dihydro-7-methyl-12-ethyl-pyrido[2,3-b]pyrido [2,3-4,5]thieno[2,3-f][1,4]diazepin-6(12H)-thione (MEN 10979) enhanced the anti-HIV-1 activity of AZT and dideoxyinosine (ddI) in a synergistic manner. The new arylpyrido-diazepine and -thiodiazepine derivatives appear to be drug candidates for the treatment of HIV-1 infection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / pharmacology*
  • Azepines / chemical synthesis
  • Azepines / pharmacology*
  • Drug Evaluation, Preclinical
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV-1 / drug effects*
  • HIV-2 / drug effects*
  • Humans
  • RNA-Directed DNA Polymerase
  • Simian Immunodeficiency Virus / drug effects*
  • Structure-Activity Relationship
  • Tumor Cells, Cultured


  • Antiviral Agents
  • Azepines
  • reverse transcriptase, Human immunodeficiency virus 2
  • HIV Reverse Transcriptase
  • RNA-Directed DNA Polymerase