Identification of sulfamoylbenzamide derivatives as selective cathepsin D inhibitors

Aspartic proteases play very important role in post translational processing of proteins and several of them are essential for organism's viability. Here we present the enzyme inhibition activities of different Sulfamoylbenzamide derivatives against two aspartic proteases cathepsin D and plasmepsin II. Cathepsin D is an aspartic protease that degrades proteins at acidic pH in the lysosomes, or extracellular matrix. It is overexpressed by epithelial breast cancer cells and hence hyper-secreted. On the other hand plasmepsin II is an essential enzyme of Plasmodium falciperum. Cathepsin D and Plasmepsin II are pivotal drug targets for treatment of breast cancer and malaria respectively. Virtual screening of Sulfamoylbenzamide compounds followed by enzyme inhibition assays revealed these compounds as selective Cathepsin D inhibitors while inactive against Plasmepsin-II. IC[50] values of five Sulfamoylbenzamide compounds tested are in range of 1.25-2.0 microM. N-[3-chlorophenyl]-2-sulfamoylbenzamide is identified as the most potent of all tested Sulfamoylbenzamide compounds with IC[50] 1.25 microM. It was also noted that the docking score of theses compounds was better in case of Cathepsin D as compared to Plasmepsin-II. Docking score ranges from -29.9 +/- 1.16 to -35.1 +/- 0.13 in case of Cathepsin D, while from -24.0 +/- 0.10 to -29.5 +/- 0.10 in case of Plasmepsin-II