Design, synthesis, molecular docking and molecular dynamics studies of novel triazolothiadiazine derivatives containing furan or thiophene rings as anticancer agents

Bioorg Chem. 2022 May:122:105709. doi: 10.1016/j.bioorg.2022.105709. Epub 2022 Mar 1.


Breast cancer is the most common cancer type amoung post-menopausal women. Aromatase inhibitors were used in the treatment of patients. However, drug resistance may develop in long-term drug use, especially in 3rd and 4th stage (advanced) cancer cases. Therefore, there is a constant need for new agents. In this study, new triazolothiadiazine derivatives were synthesized and their anticancer activities were investigated. Compounds 2k, 2s, and 2w showed inhibitor activity against MCF-7 cell line with IC50 = 4.63 ± 0.10; 2.23 ± 0.16; 3.13 ± 0.08 µM value, respectively. As a result of in vitro aromatase enzyme inhibition test, compound 2s was the most active derivative with IC50 = 0.058 ± 0.023 µM. In addition, DNA synthesis inhibition percentages of the compounds were measured by the BrdU method. The intermolecular interactions of the promising compounds with aromatase enzyme were investigated through the SP docking approach, which revealed significant binding interaction energies associated with these compounds. Following that, the interaction's stability was assessed using a typical atomistic 100 ns dynamic simulation study. A number of parameters derived from MD simulation trajectories were computed and validated for the protein-ligand complex's stability under the dynamic conditions.

Keywords: Breast cancer; Molecular docking; Molecular dynamics; Triazolothiadiazine.

MeSH terms

  • Antineoplastic Agents* / chemistry
  • Cell Proliferation
  • Dose-Response Relationship, Drug
  • Drug Design
  • Drug Screening Assays, Antitumor
  • Female
  • Furans
  • Humans
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation*
  • Molecular Structure
  • Structure-Activity Relationship
  • Thiophenes / pharmacology


  • Antineoplastic Agents
  • Furans
  • Thiophenes
  • furan