Design, synthesis and pharmacological evaluation of 4-[2-alkylthio-5(4)-(4-substitutedphenyl)imidazole-4(5)yl]benzenesulfonamides as selective COX-2 inhibitors.
OBJECTIVE
To design and synthesize a series of benzenesulfonamide derivatives, 4-[2-alkylthio-5(4)-(4-substitutedphenyl)imidazole-4(5)-yl]benzenesulfonamides (4a-4j), which are intended to act as cyclooxygenase-2 (COX-2) inhibitors with good COX-2 inhibitor activity, and which will exert anti-inflammatory activities in vivo.


METHODS
Benzenesulfonamide derivatives were designed and synthesized through multi-step chemical reactions. All the synthesized compounds were evaluated in an in vitro assay. The active compound 4a-4f was selected for further evaluation in a carrageenan-induced rat paw edema model.


RESULTS
Docking studies showed that compound 4 bind into the primary binding site of COX-2 with the sulfonamide SO2NH2 moiety interacting with the secondary pocket amino acid residues. In the in vitro assay, compound 4 inhibited COX-2 with an inhibition concentration IC(50) value of 1.23-8 nmol/L, compared to celecoxib with IC(50) value of 1.5 nmol/L. Compound 4b and 4c had good potency and selectivity in comparison to the celecoxib. In the in vivo model, compound 4a-4f exhibited a moderate potency to inhibit 50% carrageenan-induced paw edema with value of 1.58-4.3 mg/kg. In the latter experiment, compound 4c was the most active compound.


CONCLUSIONS
The anti-inflammatory effects obtained for compound 4a-4j could be due to the presence of fluorine or hydrogen substituents in the para position of the phenyl ring of these compounds.
Salimi
Mona
M
Research and Development Center, Pasteur Institute of Iran, Kasas, Iran.
Ghahremani
Mohammad Hossein
MH
Naderi
Nima
N
Amini
Mohsen
M
Salimi
Elika
E
Amanlou
Massoud
M
Abdi
Khosrou
K
Salehi
Raha
R
Shafiee
Abbas
A
D000818:Animals; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D015195:Drug Design; D007093:Imidazoles / Q000138:chemical synthesis / Q000494:pharmacology; D008297:Male; D008958:Models, Molecular; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology
D052246:Cyclooxygenase 2 Inhibitors; D007093:Imidazoles; D013449:Sulfonamides