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.
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.
Kukla
M J
MJ
Janssen Research Foundation, Spring House, Pennsylvania 19477.
Breslin
H J
HJ
Pauwels
R
R
Fedde
C L
CL
Miranda
M
M
Scott
M K
MK
Sherrill
R G
RG
Raeymaekers
A
A
Van Gelder
J
J
Andries
K
K
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
D000998:Antiviral Agents; D001570:Benzodiazepinones