Discovery of 3-(4-bromophenyl)-6-nitrobenzo[1.3.2]dithiazolium ylide 1,1-dioxide as a novel dual cyclooxygenase/5-lipoxygenase inhibitor that also inhibits tumor necrosis factor-alpha production.
In the present study we have discovered compound 1, a benzo[1.3.2]dithiazolium ylide-based compound, as a new prototype dual inhibitor of cyclooxygenase (COX) and 5-lipoxygenase (5-LOX). Compound 1 was initially discovered as a COX-2 inhibitor, resulting indirectly from the COX-2 structure-based virtual screening that identified compound 2 as a virtual hit. Compounds 1 and 2 inhibited COX-1 and COX-2 in mouse macrophages with IC(50) in the range of 1.5-18.1microM. Both compounds 1 and 2 were also found to be potent inhibitors of human 5-LOX (IC(50)=1.22 and 0.47microM, respectively). Interestingly, compound 1 also had an inhibitory effect on tumor necrosis factor-alpha (TNF-alpha) production (IC(50)=0.44microM), which was not observed with compound 2. Docking studies suggested the (S)-enantiomer of 1 as the biologically active isomer that binds to COX-2. Being a cytokine-suppressive dual COX/5-LOX inhibitor, compound 1 may represent a useful lead structure for the development of advantageous new anti-inflammatory agents.
Chen
Chien-Shu
CS
School of Pharmacy, National Taiwan University, Taipei 100, Taiwan.
Tan
Chen-Ming
CM
Huang
Chiung-Hua
CH
Chang
Ling-Chu
LC
Wang
Jih-Pyang
JP
Cheng
Fong-Chi
FC
Chern
Ji-Wang
JW
D000818:Animals; D052160:Benzothiazoles; D002460:Cell Line; D018360:Crystallography, X-Ray; D003499:Cyclic S-Oxides; D051545:Cyclooxygenase 1 / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D055808:Drug Discovery; D006801:Humans; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009574:Nitro Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
C548616:3-(4-bromophenyl)-6-nitrobenzo(1.3.2)dithiazolium ylide 1,1-dioxide; D052160:Benzothiazoles; D003499:Cyclic S-Oxides; D016861:Cyclooxygenase Inhibitors; D016859:Lipoxygenase Inhibitors; D009574:Nitro Compounds; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2