Synthesis, biological evaluation and molecular modeling of 1,3,4-thiadiazol-2-amide derivatives as novel antitubulin agents

Bioorg Med Chem. 2014 Aug 1;22(15):4312-22. doi: 10.1016/j.bmc.2014.05.017. Epub 2014 May 17.

Abstract

A series of 1,3,4-thiadiazol-2-amide derivatives (6a-w) were designed and synthesized as potential inhibitors of tubulin polymerization and as anticancer agents. The in vitro anticancer activities of these compounds were evaluated against three cancer cell lines by the MTT method. Among all the designed compounds, compound 6f exhibited the most potent anticancer activity against A549, MCF-7 and HepG2 cancer cell lines with IC₅₀ values of 0.03 μM, 0.06 μM and 0.05 μM, respectively. Compound 6f also exhibited significant tubulin polymerization inhibitory activity (IC₅₀=1.73 μM), which was superior to the positive control. The obtained results, along with a 3D-QSAR study and molecular docking that were used for investigating the probable binding mode, could provide an important basis for further optimization of compound 6f as a novel anticancer agent.

Keywords: 1,3,4-Thiadiazol-2-amide derivatives; 3D-QSAR; Anticancer activity; Molecular docking; Tubulin polymerization inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / chemical synthesis
  • Amides / chemistry*
  • Amides / pharmacology*
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Binding Sites
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Crystallography, X-Ray
  • G2 Phase Cell Cycle Checkpoints / drug effects
  • Hep G2 Cells
  • Humans
  • M Phase Cell Cycle Checkpoints / drug effects
  • MCF-7 Cells
  • Molecular Conformation
  • Molecular Docking Simulation
  • Protein Structure, Tertiary
  • Quantitative Structure-Activity Relationship
  • Tubulin Modulators / chemical synthesis*
  • Tubulin Modulators / chemistry
  • Tubulin Modulators / pharmacology*

Substances

  • Amides
  • Antineoplastic Agents
  • Tubulin Modulators