Structure-activity relationships of 6-nitroquinazolines: dual-acting compounds with inhibitory activities toward both TNF-alpha production and T cell proliferation.
We synthesized various 6-nitroquinazolines by modifying the structure of compound 1 and evaluated their inhibitory activities toward both TNF-alpha production and T cell proliferation responses. The presence of the unsubstituted piperazine ring at the C(7)-position was required for both inhibitory activities. In this series of compounds, 5d and 5f, containing the 4-fluorophenyl and 3,4-difluorophenyl moiety, respectively, at the C(4)-position, showed the suppressing effects toward both responses with low cell growth inhibition. Furthermore, the oral administration of these compounds mentioned above at doses of 30 and 100 mg/kg also resulted in significant inhibition of TNF-alpha production induced by LPS in vivo.
Tobe
Masanori
M
Pharmaceuticals & Biotechnology Laboratory, Japan Energy Corporation, Saitama, Japan.
Isobe
Yoshiaki
Y
Tomizawa
Hideyuki
H
Nagasaki
Takahiro
T
Obara
Fumihiro
F
Matsumoto
Mitsuhiro
M
Hayashi
Hideya
H
D000818:Animals; D004353:Drug Evaluation, Preclinical; D006131:Growth Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009600:Nitroquinolines / Q000737:chemistry* / Q000494:pharmacology*; D011799:Quinazolines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
D006131:Growth Inhibitors; D009600:Nitroquinolines; D011799:Quinazolines; D014409:Tumor Necrosis Factor-alpha