Design, Synthesis and Pharmacological screening of Indomethacin analogues as selective COX-2 inhibitors

Abstract

Comparative molecular field analysis (CoMFA) and Comparative molecular similarity indices analysis (CoMSIA) was performed for 49 indomethacin analogues which includes aliphatic and arylalkyl amide derivatives, aromatic and heterocyclic amide derivatives and substituted indomethacin esters and amides in order to design selective COX-2 inhibitors using SYBYL-X-1.2 from Tripos Inc. St. Louis, MO, USA. The models were validated for their statistical significance by means of Partial least square (PLS) analysis. The studies produced models with good correlation and coefficients and predictive ability which were used to predict the activity of the designed compounds. Molecular docking study was also performed on Surflex-Dock of SYBYL-X-1.2 for designed compounds to analyze receptorligand interactions that confer the selectivity for COX-2. There are some strong hydrogenbonding interactions observed between amino acid residues Arg120, Tyr355, His90, Ser530 and Leu352. Based on docking study as well as CoMFA and CoMSIA analysis potential designed compounds were synthesized and evaluated for their anti-inflammatory activity using carrageenan induced rat paw edema volume methods. Synthesized compounds showed good anti-inflammatory activity when compared to standard indomethacin. Keywords: CoMFA, CoMSIA, Docking, Indomethacin, Selective COX-2 inhibitors.