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

Targeting histone deacetylases (HDACs) holds significant potential for reversing aberrant epigenetic states associated with cancer and central nervous system (CNS) disorders. However, current HDAC inhibitors are limited by their poor CNS permeability. Imidazo[1,2- a ]pyridine, a benzene-fused heterocycle, exhibits antitumor activity and excellent blood–brain barrier (BBB) penetrability. Therefore, we aimed to design and synthesize a series of novel CNS-permeable HDAC inhibitors derived from imidazo[1,2- a ]pyridine, followed by a preliminary biological evaluation of the synthesized compounds. Among the compounds synthesized, IMC12 demonstrated moderate antiproliferative activity against SH-SY5Y cancer cells, with a half-maximal inhibitory concentration (IC 50 ) of 1.604 μM, which was comparable to that of the reference drug suberoylanilide hydroxamic acid (SAHA; IC 50 = 0.663 μM). Additionally, IMC12 effectively inhibited HDAC1 and HDAC6, with IC 50 values of 2891 nM and 44.41 nM, respectively. Furthermore, this compound significantly suppressed the colony-forming ability of SH-SY5Y cells, a marker indicative of carcinogenesis and metastasis. These findings suggest that IMC12 exhibits higher BBB permeability compared to SAHA. Molecular docking studies further revealed that IMC12 is more selective for HDAC6 than HDAC1. Therefore, IMC12 represents a promising candidate for cancer therapy and may be developed into a potent HDAC6-selective inhibitor. IMC12 effectively inhibited both HDAC1 and HDAC6, with IC₅₀ values of 2891 nM and 44.41 nM, respectively. Notably, the IC₅₀ value for HDAC1 was approximately 60-fold higher than that for HDAC6, indicating that IMC12 is a more potent and selective inhibitor of HDAC6. In addition, this compound suppressed the colony-forming ability of SH-SY5Y cells which has a key hallmark of carcinogenesis and metastasis. • A novel series of CNS-penetrant HDAC inhibitors featuring an imidazo[1,2 a ]pyridine scaffold were designed and synthesized. • IMC12 exhibited moderate antiproliferative activity against SH SY5Y neuroblastoma cells, with an IC₅₀ of 1.604 μM, comparable to SAHA. • IMC12 potently and selectively inhibited HDAC6 (IC₅₀ = 44.41 nM) over HDAC1 (IC₅₀ = 2891 nM), showing more than 60-fold selectivity. • IMC12 displayed favorable physicochemical properties predictive of enhanced BBB penetration (MW = 283.28, LogP = 1.94, HBD = 2, PSA = 76.38 Å 2 ) relative to SAHA. • Molecular docking and dynamics simulations revealed stable binding of IMC12 in the HDAC6 active site via Zn 2+ chelation, hydrogen bonding (Gly582), and π–π stacking (Phe643).