Design, synthesis and biological evaluation of some novel, nonpeptide caspase-1 inhibitors

Abstract

Caspase-1 is a key endoprotease responsible for the post-translational processing of pro-inflammatory cytokines mainly IL-1β, IL-18 and IL-33. Excessive secretion of IL-1β leads to various inflammatory and autoimmune diseases. Therefore, inhibition of caspase-1 may provide a potential therapeutic strategy for treatment of chronic inflammatory diseases. The present study was aimed to identify newer, nonpeptide caspase-1 inhibitors which are potent, selective and having drug like properties. For this we have employed integrated ligand based pharmacophore modeling and structure based docking studies to design newer series of N-(4-((substituted phenyl) amino)-6-methylpyrimidin-2-yl)-2 substituted phenoxy acetamide. These designed molecules were synthesized and characterized using modern spectroscopic techniques mainly IR, MASS, 1H NMR and 13C NMR. All these synthesized compounds were biologically tested for their caspase-1 inhibition potential using Caspase-1 luminance based assay. Compounds 10r, 10t, 10u, 10v, 10x and 10y showed significant enzymatic inhibition having IC50 range of 0.022 -0.078 µM. These compounds also displayed excellent cellular potency at sub-micromolar level in THP-1 cell based assay. Moreover, these compounds exhibited potential anti-inflammatory activity in carrageenan induced rat paw edema model (in vivo) with lower ulcerogenic potential. Further, the atom based 3D QSAR study revealed the effect of hydrophobic and electronic functions on the activity. All these results indicated compounds 10r, 10t, 10u, 10v, 10x and 10y could be potential leads for the development of newer caspase 1 inhibitors as anti-inflammatory agents.