Synthesis and anti-inflammatory evaluation of 9-phenoxyacridine and 4-phenoxyfuro[2,3-b]quinoline derivatives. Part 2.
Mast cells, neutrophils and macrophages are important inflammatory cells that have been implicated in the pathogenesis of acute and chronic inflammatory diseases. To explore a novel anti-inflammatory agent, we have synthesized certain 9-phenoxyacridine and 4-phenoxyfuro[2,3-b]quinoline derivatives and evaluated their anti-inflammatory activities. The title compounds were synthesized by reaction of either 9-chloroacridine or 3,4-dichlorofuro[2,3-b]quinoline with appropriate Ar-OH and their anti-inflammatory activities were studied on inhibitory effects on the activation of mast cells, neutrophils and macrophages. Four 9-(4-formylphenoxy)acridine derivatives 2b-2e were proved to be more potent than the reference inhibitor, mepacrine for the inhibition of rat peritoneal mast cell degranulation with IC(50) values of 6.1, 5.9, 13.5, and 4.7 microM, respectively. Compounds 2c, 3b, 3c, and 5a also showed potent inhibitory activity (IC(50)=4.3-18.3 microM) for the secretion of lysosomal enzyme and beta-glucuronidase from neutrophils. In addition, 2d, 3a, and 4 inhibited TNF-alpha formation from the N9 cells (the brain resident macrophages) with IC(50) vales less then 10 microM. These results indicated that acridine derivatives exhibited more potent anti-inflammatory activities than their respective furo[2,3-b]quinoline counterparts (4 vs 9; 5a vs 10a; 5b vs 10b).
Chen
Yeh-Long
YL
School of Medicinal and Applied Chemistry, College of Life Science, Kaohsiung Medical University, Kaohsiung City 807, Taiwan. yeloch@cc.kmu.edu.tw
Chen
I-Li
IL
Lu
Chih-Ming
CM
Tzeng
Cherng-Chyi
CC
Tsao
Lo-Ti
LT
Wang
Jih-Pyang
JP
D000166:Acridines / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000494:pharmacology; D015550:Cell Degranulation / Q000187:drug effects; D002460:Cell Line / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D005966:Glucuronidase / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008407:Mast Cells / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects; D011804:Quinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000166:Acridines; D000894:Anti-Inflammatory Agents, Non-Steroidal; D011804:Quinolines; D014409:Tumor Necrosis Factor-alpha; D005966:Glucuronidase