Substituted methyl acridone-carboxylate derivatives as CD1/CD2 dual-targeting HDAC6 inhibitors to ameliorate the pathological phenotype of Alzheimer's disease.

Histone deacetylase 6 (HDAC6) has emerged as a promising target for Alzheimer' disease (AD). Although most reported HDAC6 inhibitors were designed to target CD2 catalytic domain, recent studies highlighted the functional importance of CD1 domain for the regulation of AD-related substrates. In this study, a series of substituted methyl acridone-carboxylate derivatives bearing a methyl ester moiety were discovered as CD1/CD2 dual-targeting HDAC6 inhibitors. The leading compound 6c could direct bind to HDAC6, and selectively inhibits HDAC6 with a high affinity in vitro. Molecular docking analysis revealed that 6c forms non-chelating coordination interactions with the zinc ions in both CD1 and CD2 domains of HDAC6. 6c inhibited Aβ oligomer-induced microtubule depolymerization and microglial phagocytic impairments in vitro. Furthermore, 6c effectively prevented HDAC6-driven α-tubulin and Hsp90 deacylation, as well as cognitive impairments in Aβ1-42 oligomer-treated mice. Combined with the acceptable physicochemical properties and promising biosafety of 6c, this study suggested that substituted methyl acridone-carboxylate derivatives, as CD1/CD2 dual-targeting HDAC6 inhibitors, might be developed as a novel lead drug for the treatment of AD.