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.
abstract: A series of 6-substituted 4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk][1,4]benzodiazepin- 2(1H)-ones (9) have been synthesized and tested for their ability to inhibit the replication of the HIV-1 virus in MT-4 cells. Two synthetic methods are described, one of which allows the synthesis of single enantiomers of the final products. A structure-activity study was done within the series of compounds to determine the optimum group for the 6-position substitution and to determine whether the activity was enantiospecific at the 5-position, which was substituted with a methyl group. The best analogue, 9jj, inhibited HIV-1 with an IC50 of 4 microM, which is comparable to the activity level of DDI, a 2',3'-dideoxynucleoside-type structure undergoing clinical trials as an anti-AIDS therapy.
authors.affiliation: Janssen Research Foundation, Spring House, Pennsylvania 19477.
authors.forename: M J
authors.initials: MJ
authors.lastname: Kukla
authors.forename: H J
authors.initials: HJ
authors.lastname: Breslin
authors.forename: R
authors.initials: R
authors.lastname: Pauwels
authors.forename: C L
authors.initials: CL
authors.lastname: Fedde
authors.forename: M
authors.initials: M
authors.lastname: Miranda
authors.forename: M K
authors.initials: MK
authors.lastname: Scott
authors.forename: R G
authors.initials: RG
authors.lastname: Sherrill
authors.forename: A
authors.initials: A
authors.lastname: Raeymaekers
authors.forename: J
authors.initials: J
authors.lastname: Van Gelder
authors.forename: K
authors.initials: K
authors.lastname: Andries
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001570:Benzodiazepinones / Q000138:chemical synthesis* / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D006678:HIV / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D001570:Benzodiazepinones