Novel imidazolyl-hydroxamic acid Schiff base scaffold derivatives as histone deacetylase inhibitors: Design, synthesis, and biological assessment

Histone deacetylases (HDACs) are important therapeutic targets for Cancer. A series of new imidazolyl-hydroxamic acid Schiff base scaffold derivatives have been meticulously developed and synthesized with the goal of inhibiting histone deacetylase (HDAC). These compounds are characterized by three units: an imidazolyl as the cap, linked to a 4-amino-benzamido group as a linker and an N-hydroxyl head as metal-binding unit. Following a rigorous multistep synthesis process, we successfully produced seven new imidazolyl-hydroxamic acid Schiff base derivatives (6a-g). The structure of these compounds was validated through various approaches, including ¹H NMR, ¹³C NMR, IR, mass spectrometry, and elemental analysis. We subsequently evaluated the cytotoxic effects of these synthesized derivatives against seven cell lines. This assessment included human Cancer cell lines including MCF-7 (breast Cancer), HT29 (colon Cancer), HepG2 (hepatocellular carcinoma), A2780 (ovarian Cancer), and A2780cis (cisplatin-resistant ovarian Cancer). Additionally, we examined cytotoxicity of derivatives (6a-g) against the murine mammary carcinoma cell line (4T1) and a control normal cell line, CHO (Chinese hamster ovary). All of the seven derivatives were tested for their inhibitory activity against pan-HDAC in the A2780 cell line. Among these, 6g demonstrated significant cytotoxicity compared to the Other derivatives in almost all tested Cancer cell lines. Analysis indicated that treatment with 6g significantly elevated cell Apoptosis in the A2780 Cancer cells (IC₅₀ = 8.10 μM), evidenced by Annexin V-FITC/propidium iodide staining. Furthermore, 6g notably reduced colony formation in MCF-7 Cancer cells and decreased migration in A2780 Cancer cells. In addition, 6g showed an antiangiogenic effect similar to that of Vorinostat in the chick chorioallantoic membrane (CAM) model at a quantity of 5 μM. In vivo efficacy assessments conducted on the 4T1 breast Cancer mouse model utilizing female Balb/c mice in which 6g (50 mg/kg, every Other day, i.p.) demonstrated better efficacy compared to Vorinostat. To explore the interactions and stability of the HDAC-ligand complex, we applied docking and molecular dynamic simulation studies. These findings indicated that 6g could be considered as an effective cure in treatment of solid tumors.

Cancer; Histone deacetylase inhibitor; Imidazole; Schiff base; Small-molecule.