Design and synthesis of novel celecoxib analogues as selective cyclooxygenase-2 (COX-2) inhibitors: replacement of the sulfonamide pharmacophore by a sulfonylazide bioisostere.
A group of celecoxib analogues in which the para-SO(2)NH(2) substituent on the N(1)-phenyl ring was replaced by a para-sulfonylazido (SO(2)N(3)) 4, or a meta-SO(2)N(3) 8, substituent were designed for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro COX-1 and COX-2 inhibition studies showed that 4-[5-(4-methylphenyl)-3-trifluoromethyl-1H-pyrazol-1-yl]benzenesulfonyl azide (4) with a para-SO(2)N(3) substituent was a selective COX-1 inhibitor. In contrast, 3-[5-(4-methylphenyl)-3-trifluoromethylpyrazol-1-yl]benzenesulfonyl azide (8a) having a meta-SO(2)N(3) substituent (COX-1 IC(50) >100microM; COX-2 IC(50)=5.16microM; COX-2 selectivity index >19.3) is a selective COX-2 inhibitor. A molecular modeling (docking) study showed that the SO(2)N(3) group of 8a inserts deep inside the secondary pocket of the COX-2 binding site. The SO(2)N(3) moiety of 8a can undergo a dual H-bonding interaction via one of its SO(2) oxygen-atoms, and an electrostatic (ion-ion) interaction via the terminal azido (N(3)) nitrogen-atom, to the guanidino NH(2) of Arg(513) in the secondary pocket of COX-2. These observations indicate that an appropriately positioned SO(2)N(3) moiety is a novel alternative bioisostere to the traditional SO(2)NH(2) and SO(2)Me pharmacophores present in selective COX-2 inhibitors, that are only capable of H-bonding interactions with the COX-2 isozyme, for use in drug design.
Uddin
Md Jashim
MJ
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada T6G 2N8.
Rao
P N Praveen
PN
Knaus
Edward E
EE
D001386:Azides / Q000737:chemistry*; D000068579:Celecoxib; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007527:Isoenzymes / Q000187:drug effects*; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects*; D011720:Pyrazoles; D013057:Spectrum Analysis; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology*
D001386:Azides; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D011720:Pyrazoles; D013449:Sulfonamides; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D000068579:Celecoxib