Design, synthesis, biological evaluation and molecular modeling studies of novel diazole derivatives containing methylsulfonyl pharmacophoric moiety as selective COX-2 inhibitors

Abstract

Introduction: Inflammatory diseases are one of the most common conditions in human societies and cover a wide range of diseases. The prim aim in control of inflammation is alleviation of pain it causes. The control of inflammation also prevents possible damages to the organs. Aims: According to the literature, inflammation and, diseases and injuries caused by inflammation are one of the most important causes of death in the world. An effective way for control of inflammation is the inhibition of cyclooxygenase-2, which has low side effects. Therefore, the design, synthesis and biological evaluation of compounds that can effectively inhibit the enzyme cyclooxygenase-2 constitute a valuable approach. Methods: In this study, based on the available structure-activity relationship, pyrazoline derivatives were designed, synthesized and biologically evaluated. The inhibitory potency of synthesized compounds on COX-1 and COX-2 isoenzymes was evaluated. MTT assay was also performed to evaluate cytotoxicity of the compounds against colon adenocarcinoma cells. Finally, the interaction of synthesized compounds with the active site of cyclooxygenase-2 was investigated by molecular docking studies. Results: The target compounds were synthesized and characterized by IR, 1H-NMR, 13C-NMR, mass and elemental analysis methods. Moreover, the results of biological tests showed that all of the sunthesized derivatives were selective for COX-2 and among them, compound 11 showed the highest inhibitory effect for COX-2 enzyme with IC50 value of 50 nM. In addition, compound 11 showed good cytotoxicity against colorectal adenocarcinoma cells (HT-29). Furthermore, based on molecular docking studies, it was shown that the orientation of the synthesized compounds in the active site of COX-2 is similar to that of known coxibs. Conclusion: The findings of the current study showed that the pyrazoline structure is a useful scaffold with COX-2 inhibitory activity. Such pyrazoline based scaffolds can be used for designing and developing of structures where inhibition of COX-2 enzyme is needed.