Design and Synthesis of Piperidine Hydroxamate Scaffolds as Novel HDAC Inhibitors with Apoptotic Potential in Human Cervical Cancer Cells.

INTRODUCTION

Histone deacetylase (HDAC) inhibitors are redefining cancer treatment paradigms by targeting epigenetic mechanisms, reactivating tumour suppressor genes, and promoting apoptosis in malignant cells. This study was designed to synthesize and evaluate novel piperidine hydroxamate scaffolds as potent HDAC inhibitors with specific apoptotic activity against cervical cancer cells.

METHODS

The structure-based design systematic approach was employed and anticipated druglikeness, physicochemical features, pharmacokinetic profiling, molecular docking, and molecular dynamics simulations to guide the synthesis of piperidine hydroxamate derivatives (3a-3m). These compounds were characterised using various spectroscopic analyses, and their anticancer efficacy was assessed through in-vitro evaluation using an HDAC-8 inhibitory assay and MTT assay on the HeLa cervical cancer cell line.

RESULTS

Computational analyses revealed robust binding interactions of the compounds with critical HDAC-8 residues, supported by favourable pharmacokinetic profiles. By specifically targeting HDAC-8 in cervical cancer cells, compound 3l (N-hydroxy-1-[(2E)-2-(2-hydroxybenzylidene) hydrazinyl] carbonothionyl] piperidine-4-carboxamide) was found to be the most significant one, with its IC50 value of 58.89 nM, revealing its anticancer effectiveness.

DISCUSSION: The synthesised scaffolds exhibited high specificity and significant apoptotic effects on selective inhibition of HDAC-8, which substantiates their potency in cervical cancer therapy. The effectiveness of compound 3l shows the importance of hydroxamate derivatives because they bind to zinc ions in HDAC-8. This interrupts key cancer-related processes and encourages apoptosis by increasing pro-apoptotic proteins.

CONCLUSION

The findings of this research underscore the therapeutic potential of piperidine hydroxamate scaffolds, specifically compound 3l, as effective HDAC8-selective inhibitors with significant anticancer activity against cervical cancer, paving the way for future preclinical and clinical research.