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.
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.
Breslin
H J
HJ
Janssen Research Foundation, Spring House, Pennsylvania 19477.
Kukla
M J
MJ
Ludovici
D W
DW
Mohrbacher
R
R
Ho
W
W
Miranda
M
M
Rodgers
J D
JD
Hitchens
T K
TK
Leo
G
G
Gauthier
D A
DA
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
D000998:Antiviral Agents; D007093:Imidazoles; D001569:Benzodiazepines