Key structural requirements of benzamide derivatives for histone deacetylase inhibition: design, synthesis and biological evaluation

Abstract

Background: Histone deacetylase inhibitors (HDACIs) are important as anticancer agents. Objective: This study aimed to investigate some key structural features of HDACIs via the design, synthesis and biological evaluation of novel benzamide-based derivatives. Methods: Novel structures, designed using a molecular modification approach, were synthesized and biologically evaluated. Results: The results indicated that a subset of molecules with CH₃/NH₂ at R₂ position possess selective antiproliferative activity. However, only those with an NH₂ group showed HDACI activity. Importantly, the shorter the molecule length, the stronger HDACI. Among all, 7j was the most potent HDAC1-3 inhibitor and antiproliferative compound. Conclusion: The results of the present investigation could provide valuable structural knowledge applicable for the development of the HDACIs and benzamide-based antiproliferative agents in the future.

Summary points

• Novel benzamide-based structures were designed by modifying the length of molecules and varying substitutions on the terminal benzene rings of the core scaffold.

• The designed compounds were synthesized.

• Class I histone deacetylase inhibitor (HDACI) potencies of designed compounds were evaluated. According to the results, the compounds with an NH₂ group in the R₂ position and a shorter molecular length are potent HDACIs.

• The antiproliferative activity of the designed compounds was evaluated on MCF-7 and T₄7D cells. The results showed that molecules with either CH₃ or NH₂ at the R₂ position possessed selective antiproliferative activity against cancer cells.

• Compound 7j was the most potent HDACI and antiproliferative in the synthesized compounds of this study.

• Two new potent antiproliferative molecules were proposed using a quantitative structure–activity relationship study.

• Docking of synthesized compounds on HDAC2 revealed that 7j establishes more interactions with the enzyme, which is almost identical to those shown experimentally for 2-aminobenzamide.

• Analyses of the root-mean-square deviation and potential energy plots during molecular dynamics simulation for the complexes of HDAC2 with those ligands showed stability for the proposed docked models.

• Drug likeness features of 7g and 7j compounds fit with Lipinski rules.

Keywords: :

• breast cancer
• histone deacetylase inhibitors
• molecular docking
• molecular dynamics simulation
• QSAR
• structure modification
• synthesis

Author contributions

N Cheshmazar: investigation, carried out the experiments, data analysis and writing the original draft of paper; Maryam Hamzeh-Mivehroud: docking and MTT assay; S Hemmati: synthesis; H Abolhasani and F Heidari: MTT assay; HN Charoudeh: biologic evaluation; M Zessin and M Schutkowski: enzyme-based biologic evaluation; W Sippl: enzyme-based biologic evaluation and writing – review and editing; S Dastmalchi: project administration, supervision, data analysis, writing – review and editing.

Financial disclosure

The authors would like to thank the Research Office and Biotechnology Research Center of Tabriz University of Medical Sciences for providing financial support under the Postgraduate Research Grant scheme for the PhD thesis of Narges Cheshmazar (grant no. 60360). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

The authors would like to thank the Research Office and Biotechnology Research Center of Tabriz University of Medical Sciences for providing financial support under the Postgraduate Research Grant scheme for the PhD thesis of Narges Cheshmazar (grant no. 60360).