Design, synthesis, structural characterization, in vitro anticancer activity, and in silico studies of some new hydroxylated and fluorinated-substituted hydrazone derivatives

OpenAlex · İngilizce

Today, due to improved lifestyles and increased survival, the number of new cancer cases and cancer-related deaths continues to increase. In this study, novel hydroxylated and fluorinated-substituted hydrazone derivatives bearing an aromatic nitro moiety ( 2a - d and 3a - d ) were designed as potential anticancer drug candidates, synthesized for the first time, and evaluated for their anticancer activity against chondrosarcoma (SW1353), a common primary malignant cartilage-forming tumor, neuroblastoma (SH-SY5Y), a type of brain cancer, and healthy (L929) cell lines using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) method for 24 h. The chemical structures of the target molecules were confirmed by FT-IR, 1D NMR ( 1 H- and 13 C- NMR, and APT), 2D NMR (COSY, HETCOR, and HMBC), and elemental analysis. Some of the compounds targeted against these cancer cell lines showed activity greater than 200 μM, whereas others ( 2d and 3a ) demonstrated significant cytotoxic activity. Among them, compound 3a (IC 50 = 9.45 ± 2.14 μM), a fluorinated-substituted hydrazone derivative, showed significant cytotoxic activity against the human SW1353 cell line compared to cisplatin (IC 50 = 11.9 ± 0.95 μM). The anti-migratory properties of compounds 2d and 3a in SW1353 cells, were investigated. In particular, compound 3a exhibited anti-migration behavior in SW1353 cells, with a wound closure rate of 22.25 % compared with control cells. Further, scaffolds 2d and 3a exhibited the best docking with target receptor proteins 2OH4 (−8.3 and −8.4 kcal/mol) and 3QX3 (−12.2 and 11.0 kcal/mol), thereby supporting our bioactivity studies. Compounds 2a, 3a, 3b , and 3c showed high gastrointestinal (GI) absorption, with all except 3a being non-permeable to the blood-brain barrier (BBB). Most compounds, except 3d , are non-substrates of P-glycoprotein (P-gp). In conclusion, the in vitro and in silico results of some of the tested compounds indicate that they could be promising molecular frameworks for further studies.