Appraisal of GABA and PABA as linker: Design and synthesis of novel benzamide based histone deacetylase inhibitors

Histone deacetylase inhibitors have been actively explored as a new generation of chemotherapeutics for cancers, generally known as epigenetic therapeutics. Two novel series of N-(2-amino-phenyl)-4-{[(2/3/4-substituted-phenylcarbamoyl)-methyl]-amino}-butyramide and N-(2-amino-phenyl)-4-{[(2/3/4-substituted-phenylcarbamoyl)-methyl]-amino}benzamide were designed and synthesized as novel histone deacetylase inhibitors. The anticancer potential of the compounds were determined in-vitro using MTT assay against HCT-116 and U251 (glioma) cell lines and histone deacetylase inhibitory assay. The synthesized compounds were investigated for anti-tumor activity against Ehrlich ascites carcinoma (EAC) cells in Swiss albino mice. The efforts were also made to ascertain structure–activity relationships among test compounds. The results of the present studying represents appraisal of γ-aminobutyric acid (GABA) and para-aminobenzoic acid (PABA) as linker moiety for development of newer benzamide based histone deacetylase inhibitor.

Graphical abstractBenzamides possessing linker derived from GABA/PABA were designed and synthesized to meet structural requirements necessary for HDAC inhibitors i.e., zinc binding group (C), linker (B) and surface recognition group (A).Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Anticancer activity determined using MTT assay (HCT-116 and U251 cell lines). ► These benzamide based HDAC inhibitors were subjected to HDAC inhibitory assay. ► Antitumor evaluation of benzamide analogs against EAC cells in Swiss albino mice. ► Efforts were also made to disclose SAR among benzamide based HDAC inhibitors. ► Results represents appraisal of GABA/PABA as linker for design of HDAC inhibitors.