Design, synthesis and biological evaluation of coumarin-based HDAC6 inhibitors for the treatment of ulcerative colitis.

Novel selective histone deacetylase 6 (HDAC6) inhibitors using coumarin moiety as the cap were designed, synthesized and evaluated for HDAC enzymatic assays and anti-inflammatory tests. Among them, compound 24 emerged as the most promising candidate, demonstrating potent HDAC6 inhibition with an IC50 value of 17 nM and exhibiting 32.39-fold selectivity over HDAC1. In vitro studies revealed that compound 24 efficiently suppressed nitric oxide production in RAW264.7 mouse macrophages, with an IC50 value of 2.31 μM. Furthermore, human liver microsome tests confirmed its excellent metabolic stability, with a half-life of 59.74 min. Following administration at 30 mg/kg, compound 24 effectively maintain the integrity of colon tissue of DSS-induced ulcerative colitis mice model. Notably, its therapeutic efficacy was comparable to that of tofacitinib. These findings suggested that compound 24 was a promising anti-inflammatory candidate for selective HDAC6 inhibitor and deserves further investigation.