title: Synthesis and anti-HIV-1 activity of 4,5,6,7-tetrahydro-5-methylimidazo [4,5,1-jk][1,4]benzodiazepin-2(1H)-one (TIBO) derivatives. 3.
abstract: 4,5,6,7-Tetrahydro-5-methylimidazo[4,5,1-jk][1,4]benzodiazepin-2 (1H)-ones (TIBO), 1, have been shown to significantly inhibit HIV-1 replication in vitro by interfering with the virus's reverse transcriptase enzyme. They have also demonstrated potential clinical efficacy in combating HIV-1, on the basis of a preliminary study. Our prior publications have discussed the discovery of this series of compounds and reported some preliminary chemical and biological studies around N-6 substitutions and 5-membered ring variations of 1. This manuscript describes our synthetic endeavors around 4, 5, and 7 mono- and disubstitutions of 1 and discusses related HIV-1 inhibitory structure-activity relationships. On the basis of inhibition of HIV-1's cytopathic effects in MT-4 cells, we found that 5-mono-Me-substituted analogues, the original substitution in the early lead compounds, and 7-mono-Me-substituted analogues of 1 were comparable as being consistently the most active compounds. Although generally less active, the 4,5,7-unsubstituted, 4-mono-substituted, cis- and trans-5,7-di-Me-substituted, and cis-4,5-di-Me-substituted analogues of 1 also exhibited some significant desired activity. The remaining trans-4,5-di-Me-substituted, cis- and trans-4,7-di-Me-substituted, and all 4,5-, 5,6-, 6,7-, and 7,8-fused disubstituted analogues of 1 possessed no noticeable desired activity.
authors.affiliation: Janssen Research Foundation, Spring House, Pennsylvania 19477.
authors.forename: H J
authors.initials: HJ
authors.lastname: Breslin
authors.forename: M J
authors.initials: MJ
authors.lastname: Kukla
authors.forename: D W
authors.initials: DW
authors.lastname: Ludovici
authors.forename: R
authors.initials: R
authors.lastname: Mohrbacher
authors.forename: W
authors.initials: W
authors.lastname: Ho
authors.forename: M
authors.initials: M
authors.lastname: Miranda
authors.forename: J D
authors.initials: JD
authors.lastname: Rodgers
authors.forename: T K
authors.initials: TK
authors.lastname: Hitchens
authors.forename: G
authors.initials: G
authors.lastname: Leo
authors.forename: D A
authors.initials: DA
authors.lastname: Gauthier
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000494:pharmacology*; D002460:Cell Line; D015497:HIV-1 / Q000187:drug effects*; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D007093:Imidazoles; D001569:Benzodiazepines