Design, synthesis and mechanistic studies of benzophenones hydrazone derivatives as cathepsin inhibitors

Abstract

A novel series of benzophenone hydrazone derivatives were synthesized and evaluated for their antiproliferative activity. The thiosemicarbazone derivative 5c and guanylhydrazone derivatives 6d-f showed potent antiproliferative activities against A498 renal cancer cells with IC50= 14.5, 0.28, 0.30 and 0.3 µM, respectively. Compounds 5c, 6d, 6e and 6f showed inhibitory activities against cathepsin L and cathepsin B (IC50 ranged from 0.071 to 0.303 µM. A mechanistic study revealed that compound 6e induced apoptosis on A498 cell line by 38.02% compared to 1.64% in control. This apoptotic effect was supported by an 8.58-fold increase in the level of caspase-3 compared to the control cells. Additionally, compound 6e inhibited A498 cell growth mostly at the S phase. Furthermore, molecular modeling studies showed that compound 6e possessed good fitting with cathepsin L and cathepsin B binding sites through their interaction with essential amino acids through hydrophobic H-bonding interactions. Therefore, compound 6e could be considered as a prospective anticancer lead compound and it worth further exploration/optimization as an antiproliferative agent via cathepsins inhibition.