Synthesis, Cyclooxygenase-2 Inhibition, Anti-inflammatory Evaluation and Docking Study of Substituted-N-(3,4,5-trimethoxyphenyl)-benzo[d]oxazole Derivatives.

BACKGROUND

Non-steroidal anti-inflammatory drugs are widely used for many years, but the chronic use of NSAID's leads to gastric side effects, ulceration and kidney problems. These side effects are due to non-selective inhibition of COX-2 along with COX-1. Therefore, it is imperative to develop novel and selective COX-2 inhibitors.

OBJECTIVE

In this paper wehave synthesized a series of novel hybrids comprising of substituted-N- (3,4,5-trimethoxyphenyl)-benzo[d]oxazole derivatives and screened for the treatment of inflammation.

METHODS

The structures of the obtained compounds were elucidated by elemental and spectral analysis (ATR-FTIR, 1H NMR, 13C NMR, Mass spectroscopy). All of the compounds were evaluated for cyclooxygenase (COX-1/COX-2) inhibitory activity by in vitro enzymatic assay. The compound which showed COX-2 activity (3a - 3e, 3g - 3h, 3k, 3m and 3o) was further screened for in vivo anti-inflammatory activity and ulcerogenic liability. Molecular docking study was also performed with resolved crystal structure of COX-2 to understand the binding mechanism of newly synthesized inhibitors in the active site of COX-2enzyme.

RESULTS

The in vitro COX-1 and COX-2 inhibitory studies showed that the synthesized compounds potentially inhibited COX-2 (IC50 = 0.04 - 26.41 µM range) over COX-1 (IC50 = 0.98 - 33.33 µM range). The in vivo studies predicted that compounds 3c (70.9%, 0.6±0.22), 3m (68.1%, 1.9±0.41) and 3o (70.4%, 1.7±0.27) produced more efficacy against carrageenan induced paw edema and less ulcerogenic effect, as compared to standard ibuprofen (65.9%, 2.2±0.44). The results of docking studies were found to be concordant with the biological evaluation studies of the prepared compound.

CONCLUSION

Among all the tested compounds, 2-Chloro-N-(2-(3,4,5-trimethoxyphenyl)- benzo[d]oxazol-5-yl)-benzamide (3c) was the most potent anti-inflammatory agent and has less ulcerogenic potential. This series of compound can be explored more for development of safer and more active anti-inflammatory agents.