Synthesis of Indole-Thiazolidinedione-1,2,3-triazole Conjugates as Tubulin Polymerization Inhibitors and Some in silico Studies

Abstract

In this work, new hybrid compounds (7a-o) embedded with indole, thiazolidinedione and 1,2,3-triazole pharmacophores using Cu(I) catalyzed azide alkyne cycloaddition as key approach were synthesized and characterized. All these compounds were tested for their in vitro anticancer activity against three human cancer cell lines such as A549, MCF-7 and HeLa and nocodazole was used as reference drug. Compounds 7a, 7c, 7g, 7l and 7n have shown predominant activity than nocodazole towards three cell lines with IC₅₀ values ranging from 0.3 to 1.37 µM. These five potent compounds were further screened for in vitro tubulin polymerization inhibition assay, where compounds 7c, 7g, 7l and 7n exhibited more inhibition than the standard drug combretastatin A4 (CA-4). In in silico molecular docking studies all these five compounds displayed remarkable binding energies with target protein α,β-tubulin (PDB ID: 1SA0). Further, results of in silico ADMET of the same five compounds revealed that they followed Lipinski rule, Veber rule, Egan rule and Muegge rules without any deviation and lipophilicity (Log P_o/w) of the compounds was ranging from 2.80 to 4.06. Finally, compound 7n was characterized using density functional theory (DFT) with B3LYP/6–311++G (d,p) basis set.