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

OSMANİYE D., Karaca Ş., Kurban B., BAYSAL M., Ahmad I., Patel H., ...More

BIOORGANIC CHEMISTRY, vol.122, 2022 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 122
  • Publication Date: 2022
  • Doi Number: 10.1016/j.bioorg.2022.105709
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, Biotechnology Research Abstracts, CAB Abstracts, Chemical Abstracts Core, Chimica, EMBASE, MEDLINE, Veterinary Science Database, Index Chemicus (IC)
  • Keywords: Triazolothiadiazine, Breast cancer, Molecular docking, Molecular dynamics, AROMATASE INHIBITORS
  • Anadolu University Affiliated: Yes


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 tri-azolothiadiazine 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 mu M 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 mu M. In addition, DNA synthesis inhibition percentages of the compounds were measured by the BrdU method. The intermolecular interactions of the promising compounds with ammatase 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.