2,3-Dihydroquinazolin-4(1H)-one derivatives as potential non-peptidyl inhibitors of cathepsins B and H

• Dihydroquinazolin-4(1H)-ones were evaluated as reversible non-peptidyl inhibitors.
• Inhibition to proteolysis of endogenous substrates was more at 24 h reaction.
• Inhibition type and Ki values of compounds were determined on the target enzymes.
• These structural analogs were better inhibitors for cathepsin B as compared to H.
• For some compounds, Ki value of the order of 10−9 has been determined.

A direct correlation between cathepsin expression–cancer progression and elevated levels of cathepsins due to an imbalance in cellular inhibitors-cathepsins ratio in inflammatory diseases necessitates the work on the identification of potential inhibitors to cathepsins. In the present work we report the synthesis of some 2,3-dihydroquinazolin-4(1H)-ones followed by their evaluation as cysteine protease inhibitors in general and cathepsin B and cathepsin H inhibitors in particular. 2,3-Dihydroquinazolin-4(1H)-ones, synthesized by the condensation of anthranilamide and carbonyl compound in presence of PPA-SiO2 catalyst, were characterized by spectral analysis. The designed compounds were screened as inhibitors to proteolysis on endogenous protein substrates. Further, a distinct differential pattern of inhibition was obtained for cathepsins B and H. The inhibition was more to cathepsin B with Ki values in nanomolar range. However, cathepsin H was inhibited at micromolar concentration. Maximum inhibition was shown by compounds, 1e and 1f for cathepsin B and compounds 1c and 1f for cathepsin H. The synthesized compounds were established as reversible inhibitors of cathepsins B and H. The results were also compared with the energy of interaction between enzyme active site and compounds using iGemdock software.

The present study reports 2,3-dihydroquinazolin-4(1H)-one derivatives as cysteine cathepsin inhibitors. Maximum inhibitory effect was exerted by compounds 1f and 1e for cathepsin B and 1c and 1f for cathepsin H.Figure optionsDownload as PowerPoint slide