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Arylamide as Potential Selective Inhibitor for Matrix Metalloproteinase 9 (MMP9): Design, Synthesis, Biological Evaluation, and Molecular Modeling

Previous studies have reported that compounds bearing arylamide linked to heterocyclic planar ring, have successfully inhibit the hemopexin-like domain (PEX9) of matrix metalloproteinase9 (MMP9). PEX9 has been suggested to be more selectively targeted than MMP9's catalytic domain in degrading extracellular matrix in some pathologic conditions, especially in cancer. In this study, we aim to synthesize and evaluate ten arylamide compounds as MMP9 inhibitors through enzymatic assay as well as cellular assay. The mechanism of inhibition for the most active compounds was investigated by molecular dynamics simulation (MD). Molecular docking was performed using AutoDock4.0 with PEX9 as the protein model to predict the binding of the designed compounds. The synthesis was carried out by reacting aniline derivatives with 3-bromopropanoyl chloride using pyridine as the catalyst at room temperature. MMP9 assay was conducted using FRET-based MMP9 kits protocol and gelatin zymography assay. Cytotoxicity assay was done using MTT method and the MD simulation was performed using AMBER16. Assay on MMP9 demonstrated activities of three compounds (2, 7 and 9) with more than 50% inhibition. Further inhibition on MMP9 expressed by 4T1 showed two compounds (7 and 9) inhibited its gelatinolysis activity for more than 50%. The cytotoxicity assay against 4T1 cell results in the inhibition of the cell growth with EC50 of 125 μM and 132 μM for 7 and 9, respectively. MD simulation explained a stable interaction of 7 and 9 in PEX9 at 100 ns with the free energy of binding: -46.5 kcal/mol and -36.9 kcal/mol, respectively. Arylamides have potential effects as selective MMP9 inhibitors in inhibiting breast cancer cell progression.