Synthesis and biological evaluation of 3-[4-(amino/methylsulfonyl)phenyl]methylene-indolin-2-one derivatives as novel COX-1/2 and 5-LOX inhibitors.
Fourteen new 3-[4-(amino/methylsulfonyl)phenyl]methylene-indolin-2-one derivatives were synthesized. Six compounds displayed potent inhibitory activities against COX-1/2 and 5-LOX with IC(50) in the range of 0.10-9.87 μM. Particularly, 10f exhibited well balanced inhibitory action on these enzymes (IC(50)=0.10-0.56 μM). More importantly, 10f and several other compounds had comparable or stronger anti-inflammatory and analgesic activities, but better gastric tolerability in vivo, as compared with darbufelone mesilate and tenidap sodium. Therefore, our findings may aid in the design of new and safe anti-inflammatory reagents for the intervention of painful inflammatory diseases, such as rheumatoid arthritis at clinic.
Center of Drug Discovery, China Pharmaceutical University, Nanjing, PR China. lcpu333@yahoo.com.cn
Yisheng
Y
Lai
Lin
L
Ma
Wenxing
W
Huang
Xing
X
Yu
Yihua
Y
Zhang
Hui
H
Ji
Jide
J
Tian
D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001094:Arachidonate 5-Lipoxygenase / Q000737:chemistry* / Q000378:metabolism; D001597:Benzylidene Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051545:Cyclooxygenase 1 / Q000737:chemistry* / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000737:chemistry* / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D051379:Mice; D051381:Rats; D013329:Structure-Activity Relationship
D000700:Analgesics; D000893:Anti-Inflammatory Agents; D001597:Benzylidene Compounds; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007211:Indoles; D016859:Lipoxygenase Inhibitors; C456900:indolin-2-one; D001094:Arachidonate 5-Lipoxygenase; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2