Hybrids of thiazolidinone with 1,2,3-triazole derivatives: design, synthesis, biological evaluation, in silicostudies, molecular docking, molecular dynamics simulations, and ADMET profiling

AbstractA new series of thiazolidinone linked 1,2,3-triazole hybrids 5a-hwas designed and synthesized using the copper-catalyzed Huisgen azide-alkyne cycloaddition (CuAAC) between thiazolidinone linked alkyne and aromatic azides. The structures of the newly synthesized compounds were established by NMR (1H and 13C) and HRMS. The targeted thiazolidinone-1,2,3-triazole hybrids were evaluated for their cytotoxic activity against four human cancer cell lines, including fibrosarcoma (HT-1080), lung carcinoma (A-549), and breast carcinoma (MCF-7 and MDA-MB-231) using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliun bromide (MTT). The obtained data showed that most of these compounds have moderate anti-proliferative activity with IC50values between 10.26 ± 0.71 and 53.93 ± 1.20 μM. The compound 5aexhibited higher activity with an IC50value of 10.26 ± 0.71 µM, compared to 5dwith an IC50value of 11.56 ± 1.98 µM for the HT-1080 and MCF-7 cancer cells line, respectively. Moreover, Annexin-V apoptosis was assessed by flow cytometry for hybrid compounds 5a and 5d against HT-1080 and MCF-7 competitor cell lines, as they increase the level of active caspase 3/7. The experimental results were further confirmed by docking studies followed by molecular dynamic simulations. Both the potent derivatives i.e. 5aand 5dhave comparable docking scores and MD simulations results showed that the docked complex of 5ais somewhat more stable than 5dprimarily for protein p53. The ADMET profile of both derivatives established their safety zone and drug-like potential.Communicated by Ramaswamy H. Sarma