Design, synthesis and collagenase inhibitory activity of some novel phenylglycine derivatives as metalloproteinase inhibitors

作者：Ganeshpurkar Ankit; Kumar Devendra; Singh Sushil Kumar^*

来源：International Journal of Biological Macromolecules, 2018, 107: 1491-1500.

DOI：10.1016/j.ijbiomac.2017.10.008

• Clostridium histolyticum collagenase
• Phenylglycine
• Sulfonamide

Metalloproteases are a class of proteases having metal ion(s) at their catalytic sites. Bacterial collagenases are involved in human gas gangrene, periodontal diseases, food etc. The Clostridium collagenase occurs in two isoforms COLG and Col_H. The present work is based on the protein structure-based approach for the development of collagenase inhibitors. The sequence analysis and structural alignment of both isoforms showed significant similarity in active site except aspartate switch present in Col_H. The homology model was developed and validated for Col_H peptidase domain with open aspartate switch followed by the docking of designed ligands. Compound 8b showed better interaction due to the presence of the nitro group, The N-benzyl-arylsulfonyl-phenylglycine derivatives were synthesized and characterized by FTIR, H-1 NMR, C-13 NMR and mass spectral analysis. The compounds were evaluated for C. histolyticum collagenase inhibitory activity using gelatin-ninhydrin based assay. Compounds 5b, 3b, 11b, 6b and 8b with IC50 of 24.34 mu M, 29.61 mu M, 28.39 mu M, 31.4 and 32.11 mu M respectively were found to be more active. Further, The Ki of most active compound 5b was found to be 22.02 mu M showing the competitive mode of inhibition of the enzyme. The activity of the derivatives showed correlation with the docking results.

• 出版日期2018-2