Exploration of quinazoline-tethered hydroxamic acid derivatives as HDAC inhibitors for anticancer activity: Design, synthesis, molecular docking, and biological evaluation

Abstract

In the past two decades, targeted cancer therapy has emerged as a novel class of anticancer therapeutics, besides traditional chemotherapy, surgery, and radiotherapy. Inhibition of HDACs represents a promising avenue for cancer therapeutics and initial success in treating select T-cell lymphomas has led to the FDA approval of four HDAC-targeted agents. The majority of currently available HDAC inhibitors have weak anticancer activity, with significant side effects. To address these drawbacks, in the present work we have designed and synthesized a novel series of histone deacetylase inhibitors combining 2-(4-substituted phenyl) quinazoline bioactive fragment as cap group and N-hydroxycinnamamide/ N-hydroxybenzamide as linker group, and evaluated for their cytotoxic activity against the three cancer cell lines (HeLa, MCF-7 and HCT-116) and HDAC inhibitory activity. All three cancer cell lines were most sensitive to the N-hydroxyacrylamide derivatives (5a-f) as compared to N-hydroxybenzamides (7a-f) derivatives. In particular, compound 5a (0.39, 0.26, 0.41 µM respectively) and 5b (0.27, 0.57, 0.32 µM respectively) were found to be the most potent derivatives among all tested cell lines. For HDAC inhibitory activity, it was found that compounds 5a, 5b, and 5d possessed comparable, even better HDAC inhibitory activity as compared to SAHA. These compounds also tested in vitro heamolytic activity, most of the compounds found biocompatible with human erythrocytes thereby evidencing the lack of haemolytic toxicity of anticancer drugs. In silico ADMET and molecular docking studies further corroborated with the experimental results. Overall, the new synthesized compounds exhibited significant HDAC and cytotoxic activity. Also, the different substituents and unsaturated bond influenced both HDAC inhibitory and cytotoxic activity. The outcome of the current work is that several potential HDAC inhibitors have emerged for further design of more potent HDAC inhibitors with better cytotoxicity.