Design, synthesis, and biological evaluation of β-carboline 1,3,4-oxadiazole based hybrids as HDAC inhibitors with potential antitumor effects

Bioorg Med Chem Lett. 2022 May 15:64:128663. doi: 10.1016/j.bmcl.2022.128663. Epub 2022 Mar 7.

Abstract

A series of novel β-carboline 1,3,4-oxadiazole based hybrids were designed, synthesized, and tested for cytotoxicity and HDAC inhibition. Among the target compounds, compound ZDLT-1 displayed high inhibitory activity for class I HDACs 1, 2, and 3, and potent anti-proliferative activity against HCT116 cells with an IC50 value of 0.173 ± 0.018 μM, it also exhibited better inhibitory activity with an IC50 value of 6 nM for HDAC6 than SAHA (IC50 = 15 nM). Furthermore, the pharmacological experiment of Hoechst staining, colony formation, cell apoptosis assay, and wound healing scratch assay indicated that compound ZDLT-1 was a potent cytotoxic agent against HCT116 cells with cell apoptosis induction. Further, in silico prediction of physicochemical properties, drug-likeness, and ADME parameters suggested that compound ZDLT-1 is a promising anticancer agent. Taken together, the high potency cytotoxicity and class I HDACs inhibitory activity of compound ZDLT-1, which with the β-carboline 1,3,4-oxadiazole based hybrids as potent anticancer agents could be nominated for further modification and optimization.

Keywords: 1,3,4-Oxadiazole; Anticancer; HCT116 cells; HDAC; β-carboline.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents* / chemistry
  • Carbolines / chemistry
  • Carbolines / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation
  • Drug Design
  • Drug Screening Assays, Antitumor
  • Histone Deacetylase Inhibitors* / chemistry
  • Humans
  • Molecular Structure
  • Oxadiazoles
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Carbolines
  • Histone Deacetylase Inhibitors
  • Oxadiazoles
  • 1,3,4-oxadiazole