Novel Aldimine-Type Schiff Bases of 4-Amino-5-[(3,4,5- trimethoxyphenyl)methyl]-1,2,4-triazole-3-thione/thiol: Docking Study, Synthesis, Biological Evaluation, and Anti-Tubulin Activity
The present study was planned to design some novel aldimine-type Schiff bases bearing 3,4,5-trimethoxyphenyl and 1,2,4-triazole-3-thione/thiol as potential tubulin polymerization inhibitors. The obtained results of the molecular docking study using the tubulin complex (PDB code: 1SA0) showed that compounds H-25 and H-26 were well fitted in the colchicine binding site of tubulin with binding energies of 8.68 and 8.40 kcal/mol, respectively, in comparison to the main ligand (8.20 kcal/mol).
In parallel, molecular simulations were also performed on five other 3,4,5-trimethoxyphenyl-containing ligand targets including hsp90, VEGFR2, and human and microbial (Staphylococcus aureus and Candida albicans) dihydrofolate reductase, among which H-17, H-45, H-27, H-02, and H-19 were the most suitable compounds, respectively. Evaluation of the cytotoxic effect of the most efficient compounds of the docking steps (H-25) revealed IC50 values of 12.48 1.10, 4.25 0.22, 3.33 0.31, and 9.71 0.75 mM against the HT1080, HT29, MCF-7, and A549 cell lines, respectively, compared to doxorubicin (12.69 1.23, 6.12 0.47, 3.51 0.32, and 6.40 0.31 mM, respectively). The in vitro tubulin polymerization investigation launched compounds H-25 and H-26 as potent antitubulin agents due to their IC50 values of 0.17 0.01 and 10.93 0.43mM, respectively.