Discovery of Novel Imidazothiazole-Based Hydroxamic Acid Derivatives as Potent Indoleamine 2,3-Dioxygenase 1 and Histone Deacetylase 6 Dual Inhibitors

Molecules. 2025 Jun 7;30(12):2508. doi: 10.3390/molecules30122508.

Abstract

In order to take advantage of both immunotherapeutic and epigenetic antitumor agents, a series of imidazothiazole-based hydroxamic acid derivatives were designed based on the pharmacophore fusion strategy and evaluated as potent IDO1 and HDAC6 dual inhibitors. Among these inhibitors, the most potent compound 3-(4-Bromophenyl)-N-{4-[(7-(hydroxyamino)-7-oxoheptyl)amino]phenyl}imidazo[2,1-b]thiazole-5-carboxamide (10e) showed considerable IDO1 inhibitory activity and a good selectivity profile for HDAC6 over the other HDAC isoforms. The intracellular inhibition of HDAC6 by 10e was validated by Western blot analysis. Docking studies illustrated that the possible binding modes of compound 10e interacted with IDO1 and HDAC6. Moreover, compound 10e was found to arrest the cell cycle at the G2/M phase in HCT-116 cells. In particular, compound 10e also exhibited potent in vivo antitumor efficacy in CT26 tumor-bearing BALB/c mice models, with no significant toxicity. Collectively, this work provides a promising lead compound that serves as IDO1/HDAC6 dual inhibitor for the development of novel antitumor agents.

Keywords: dual inhibitors; histone deacetylase 6; hydroxamic acids; imidazo[2,1-b]thiazole; immunotherapy; indoleamine 2,3-dioxygenase 1.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Discovery
  • HCT116 Cells
  • Histone Deacetylase 6* / antagonists & inhibitors
  • Histone Deacetylase 6* / chemistry
  • Histone Deacetylase 6* / metabolism
  • Histone Deacetylase Inhibitors* / chemical synthesis
  • Histone Deacetylase Inhibitors* / chemistry
  • Histone Deacetylase Inhibitors* / pharmacology
  • Humans
  • Hydroxamic Acids* / chemical synthesis
  • Hydroxamic Acids* / chemistry
  • Hydroxamic Acids* / pharmacology
  • Imidazoles* / chemistry
  • Imidazoles* / pharmacology
  • Indoleamine-Pyrrole 2,3,-Dioxygenase* / antagonists & inhibitors
  • Indoleamine-Pyrrole 2,3,-Dioxygenase* / chemistry
  • Indoleamine-Pyrrole 2,3,-Dioxygenase* / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Molecular Docking Simulation
  • Structure-Activity Relationship
  • Thiazoles* / chemistry
  • Thiazoles* / pharmacology
  • Xenograft Model Antitumor Assays

Substances

  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Histone Deacetylase 6
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Thiazoles
  • HDAC6 protein, human
  • Antineoplastic Agents
  • IDO1 protein, human
  • Imidazoles