Design, synthesis, 3D pharmacophore, QSAR, and docking studies of carboxylic acid derivatives as Histone Deacetylase inhibitors and cytotoxic agents

• 6-(4-Substituted phenyl)-4-oxohex-5-enoic acids were synthesized.
• Compound IIf (E) displayed significant inhibitory activity against NCI Non-Small Cell Lung.
• Compounds were tested on histone deacetylase isoforms.
• 3D-pharmacophore model and QSAR were generated.

In this study, five series of (E)-6-(4-substituted phenyl)-4-oxohex-5-enoic acids IIb–f (E), (E)-3-(4-(substituted)-phenyl)acrylic acids IIIa–g (E), 4-(4-(substituted)phenylamino)-4-oxobutanoic acids VIa,b,e, 5-(4-(substituted)phenylamino)-5-oxopentanoic acids VIIa,f and 2-[(4-(substituted)phenyl) carbamoyl]benzoic acids VIIIa,e were designed and synthesized. Selected compounds were screened in vitro for their cytotoxic effect on 60 human NCI tumor cell lines. Compound IIf (E) displayed significant inhibitory activity against NCI Non-Small Cell Lung A549/ATCC Cancer cell line (68% inhibition) and NCI-H460 Cancer cell line (66% inhibition). Moreover, the final compounds were evaluated in vitro for their cytotoxic activity on HepG2 Cancer cell line in which histone deacetylase (HDAC) is overexpressed. Compounds IIc (E), IIf (E), IIIb (E), and IIIg (E) exhibited the highest cytotoxic activity against HepG2 human cancer cell lines with IC50 ranging from 2.27 to 10.71 μM. In addition, selected compounds were tested on histone deacetylase isoforms (HDAC1–11). Molecular docking simulation was also carried out for HDLP enzyme to investigate their HDAC binding affinity. In addition, generation of 3D-pharmacophore model and quantitative structure activity relationship (QSAR) models were combined to explore the structural requirements controlling the observed cytotoxic properties.

Docking model at the active site of HDLP (PDB ID: 1C3S) coincides with the generated 3D QSAR pharmacophore model for E-isomer of compound IIc (E) displaying significant antiproliferative activity against HepG2 Cancer cell line (IC50, 2.27 μM).Figure optionsDownload as PowerPoint slide