title: New arylpyrido-diazepine and -thiodiazepine derivatives are potent and highly selective HIV-1 inhibitors targeted at the reverse transcriptase.
abstract: 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.
authors.affiliation: Institute of Virology, University La Sapienza, Rome, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Bellarosa
authors.forename: G
authors.initials: G
authors.lastname: Antonelli
authors.forename: F
authors.initials: F
authors.lastname: Bambacioni
authors.forename: D
authors.initials: D
authors.lastname: Giannotti
authors.forename: G
authors.initials: G
authors.lastname: Viti
authors.forename: R
authors.initials: R
authors.lastname: Nannicini
authors.forename: A
authors.initials: A
authors.lastname: Giachetti
authors.forename: F
authors.initials: F
authors.lastname: Dianzani
authors.forename: M
authors.initials: M
authors.lastname: Witvrouw
authors.forename: R
authors.initials: R
authors.lastname: Pauwels
authors.forename: J
authors.initials: J
authors.lastname: Desmyter
authors.forename: E
authors.initials: E
authors.lastname: De Clercq
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001381:Azepines / Q000138:chemical synthesis / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects*; D015498:HIV-2 / Q000187:drug effects*; D006801:Humans; D012194:RNA-Directed DNA Polymerase; D015302:Simian Immunodeficiency Virus / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000998:Antiviral Agents; D001381:Azepines; C072416:reverse transcriptase, Human immunodeficiency virus 2; D054303:HIV Reverse Transcriptase; D012194:RNA-Directed DNA Polymerase