Design, Synthesis and Molecular Docking Study of Novel Celecoxib Derivatives Using Bioisosteric Replacement of Sulfonamide Moiety

Abstract

Celecoxib, a selective COX-2 inhibitor, is one of most commonly used nonsteroidal anti-inflammatory drug for the treatment of inflammatory symptoms. However, the presence of sulfonamide group in the structure has been suspected to cause cross-hypersensitivity with antibiotic sulfonamides. To avoid this problem, the sulfonamide moiety of celecoxib was modified using bioisosteric technique to obtain novel celecoxib derivatives. Commercially available 4,4,4-trifluoro-1-methylpheny)butane-1.3-dione was reacted with 4-hydrazinobenzonitrile HCI to obtain nitrle derivative of celecoxib (1). In addion, carboxylic acid (2) and tetrazole (3) derivatives of celecoxib were also synthesized using compound 1 as a starting material. All synthesized compounds including corresponding bioisostere groups of sulfonamide were predicted for their COX-I and COX-2 inhibitory activities by computer-based molecular docking method using AutoDock 4.2. The results showed that tetrazole derivative (3) possessed the lowest binding energy and inhibitory constant (Ki) against mCOX-2 (-9.60 kcal/mol and 91.22 nM, respectively), but lack of selectivity due to very low calculated selectivity index (SI = 0.73). Whereas hydroxymethyl derivative (7) was considered to be a selective COX-2 inhibitor (SI = 6.79). Unfortunately, all designed compounds were found to be inferior to their prototype celecoxib, which exhibited the highest potency and selectivity against mCOX-2 in this study (binding energy = = 10.4 kcal/mol, Ki = 23.91 nM, and SI = 18.14).