New racemosol derivatives as potent cyclooxygenase (COX) inhibitors.
Racemosol (1) and 10-O-demethylracemosol (2), natural products from Bauhinia malabarica Roxb., exhibit potent in vitro anti-inflammatory activities against cyclooxygenase-1 and -2 (COX-1 and -2) enzymes. To investigate the structure-activity relationship (SAR) of these molecules, we prepared and fully characterized 17 derivatives by functionalizing one, two, or all three OH group(s) of 2 (Scheme). Both the size and polarity of the substituents as well as the substitution pattern in compounds 3a-q were found to be critical for anti-inflammatory activity. The orientation of the drugs and their mode of binding were studied by molecular docking based on the known 3D structure of the complex between COX-2 and the drug SC-558. Whereas the monoacetoxy derivative 3h exhibited an equally potent inhibitory activity towards both COX-1 and -2 (Table 1), its diacetoxy congener 3i was slightly more selective toward COX-2. In vivo anti-inflammatory tests showed that 3i and 2 are slightly more active than the reference compound phenylbutazone (Table 2).
Songarsa
Saiphon
S
Department of Chemistry, Faculty of Science, Mahidol University, Rama 6 Road, Rajthevee, Bangkok 10400, Thailand.
Rajviroongit
Shuleewan
S
Sae-Tang
Darinee
D
Hannongbua
Supa
S
Kirtikara
Kanyawim
K
Kittakoop
Prasat
P
D000818:Animals; D001632:Bibenzyls / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D004487:Edema / Q000188:drug therapy / Q000201:enzymology; D051379:Mice; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley
D001632:Bibenzyls; D016861:Cyclooxygenase Inhibitors; C420866:racemosol