Dihydropyrazothiazole derivatives as potential MMP-2/MMP-8 inhibitors for cancer therapy

Bioorg Med Chem Lett. 2018 Dec 15;28(23-24):3816-3821. doi: 10.1016/j.bmcl.2018.05.004. Epub 2018 May 3.

Abstract

MMP-2/MMP-8 is established as one of the most important metalloenzymes for targeting cancer. A series of dihydropyrazothiazole derivatives (E1-E18) bearing a salicylaldehyde group linked to Pyrazole ring were designed, synthesized, and evaluated for their pharmacological activity as MMP-2/MMP-8 inhibitors. Among them, compound E17 exhibited most potent inhibitory activity (IC50 = 2.80 μM for MMP-2 and IC50 = 5.6 μM for MMP-8), compared to the positive drug CMT-1 (IC50 = 1.29 μM). Compounds (E1-E18) were scrutinized by CoMFA and CoMSIA techniques of Three-dimensional quant. structure-activity relationship (3D-QSAR), as well as a docking simulation. Moreover, treatment with compound E4 could induce MCF-7 cell apoptosis. Overall, the biological profile of E1-E18 may provide a research basis for the development of new agents against cancer.

Keywords: 3D-QSAR; Dihydropyrazothiazole; Docking simulation; MMP-2/MMP-8; Synthesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Cell Line
  • Cell Line, Tumor
  • Drug Design
  • Humans
  • Matrix Metalloproteinase 2 / metabolism*
  • Matrix Metalloproteinase 8 / metabolism*
  • Matrix Metalloproteinase Inhibitors / chemistry*
  • Matrix Metalloproteinase Inhibitors / pharmacology*
  • Molecular Docking Simulation
  • Neoplasms / drug therapy
  • Neoplasms / enzymology
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology
  • Quantitative Structure-Activity Relationship
  • Thiazoles / chemistry*
  • Thiazoles / pharmacology*

Substances

  • Antineoplastic Agents
  • Matrix Metalloproteinase Inhibitors
  • Pyrazoles
  • Thiazoles
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 8