SAR studies of differently functionalized 4′-phenylchalcone based compounds as inhibitors of cathepsins B, H and L

Abstract

Conditions related to the elevated levels of cathepsin B [3.4.22.1], cathepsin H [3.4.22.16] and cathepsin L [3.4.22.15] in various cancerous, rheumatoid arthritis and tissue degenerative disorders motivate the design, synthesis and evaluation of compounds as cathepsin B, H and L inhibitors. In the present work we report the synthesis and analysis of 36 different compounds belonging to 4 related series as cathepsin B, H and L inhibitors. After a preliminary screening of the synthesized compounds as inhibitors to the hydrolysis of endogenous protein substrates at pH 5.0, their inhibitory effects were evaluated on cathepsins B, H and L. Kinetic studies were carried out to determine the inhibition constants. It was found that the compounds belonging to different classes affected the enzyme activity significantly, and the activity was greatly affected by the presence of substituents. Maximum inhibition was caused by 2b and 2g in the cases of cathepsin B and cathepsin L, and 4d in the case of cathepsin H, where K_i values of the order of 10⁻⁸ M, 10⁻⁹ M and 10⁻⁶ M, respectively, were obtained. The results are correlated with the docking results.