Work

Design, synthesis, and biological evaluation of central nervous system penetrant histone deacetylase inhibitors derived from imidazo[1,2-a] pyridine

Year: 2025

Type: article

Abstract: Targeting histone deacetylases (HDACs) has the potential to reverse aberrant epigenetic states associated with cancer and central nervous system (CNS) disorders. However, existing HDAC inhibitors are limited by their poor CNS permeability. Imidazo[1,2-a]pyridine is a benzene heterocycle with antitumor activities and excellent BBB penetrability. Thus, we aimed to design and synthesize a series of novel central nervous system-permeable histone deacetylase (HDAC) inhibitors derived from imidazo[1,2-a]pyridine and performed a preliminary biological evaluation of the synthesized compounds. Among the synthesized compounds, IMC12 exerted the strongest antiproliferative activity against SH-SY5Y cancer cells, with a semi-inhibitory concentration (IC50) of 22.96 μM, which was superior to that of the reference drug suberoylanilide hydroxamic acid (SAHA; IC50 = 25.16 μM). It also effectively inhibited HDAC1 and HDAC6, with IC50 values of 2881 and 43.91 nM, respectively. Furthermore, this compound inhibited the colony-forming ability of SH-SY5Y cells, which is a marker of carcinogenesis and metastasis. These results suggest that IMC12 has a higher blood–brain barrier permeability than SAHA. Molecular docking studies showed that IMC12 was more selective for HDAC6 than for HDAC1. Therefore, IMC12 can be applied in cancer therapy or developed into a potent HDAC6-selective inhibitor .

Source: Results in Chemistry

DOI: 10.1016/j.rechem.2025.102954