Structure–Activity Relationships of 6-Nitroquinazolines: Dual-Acting Compounds with Inhibitory Activities toward both TNF-α Production and T Cell Proliferation

• Published in: Chemical & pharmaceutical bulletin Vol. 50; no. 8; pp. 1073 - 1080
• Main Authors: Tobe, Masanori, Isobe, Yoshiaki, Tomizawa, Hideyuki, Nagasaki, Takahiro, Obara, Fumihiro, Matsumoto, Mitsuhiro, Hayashi, Hideya
• Format: Journal Article
• Language: English
• Published: TOKYO The Pharmaceutical Society of Japan 01.08.2002; Pharmaceutical Soc Japan; Maruzen
• Subjects: 6-nitroquinazoline; Animals; Biological and medical sciences; Chemistry; Chemistry, Medicinal; Chemistry, Multidisciplinary; Drug Evaluation, Preclinical; Growth Inhibitors - chemistry; Growth Inhibitors - pharmacology; Immunomodulators; Life Sciences & Biomedicine; Lymphocyte Activation - drug effects; Male; Medical sciences; Mice; Mice, Inbred BALB C; Nitroquinolines - chemistry; Nitroquinolines - pharmacology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Physical Sciences; Quinazolines - chemistry; Quinazolines - pharmacology; Science & Technology; Structure-Activity Relationship; T cell proliferation; T-Lymphocytes - cytology; T-Lymphocytes - drug effects; T-Lymphocytes - metabolism; TNF-α production; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - biosynthesis; RHEUMATOID-ARTHRITIS; TNF-alpha production; CROHNS-DISEASE; T cell proliferation; CHIMERIC MONOCLONAL-ANTIBODY; PROINFLAMMATORY CYTOKINE; TUMOR-NECROSIS-FACTOR; POTENT; MULTIPLE-SCLEROSIS; MESSENGER-RNA; CA2; EXPRESSION; 6-nitroquinazoline; Cell proliferation; Nitro compound; Nitrogen heterocycle; Rodentia; Benzene derivatives; Cytokine; Oral administration; In vitro; Immunomodulator; In vivo; Vertebrata; Mammalia; Structure activity relation; Mouse; Animal; T-Lymphocyte; Bicyclic compound; Aromatic compound; Fluorine Organic compounds; Immunosuppressive agent; Inhibition; Piperazine derivatives; Chemical synthesis; Tumor necrosis factor α
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.50.1073

We synthesized various 6-nitroquinazolines by modifying the structure of compound 1 and evaluated their inhibitory activities toward both TNF-α 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-α production induced by LPS in vivo.