Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy and Food Chemistry, Julius Maximilian University of Würzburg, Am Hubland, Würzburg 97074, Germany.
Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, Medical University of South Carolina, Charleston, South Carolina 29425, United States.
J Med Chem. 2021 Apr 8;64(7):3794-3812. doi: 10.1021/acs.jmedchem.0c01940. Epub 2021 Mar 26.
The structures of melatonin and ferulic acid were merged into tertiary amide-based histone deacetylase 6 (HDAC6) inhibitors to develop multi-target-directed inhibitors for neurodegenerative diseases to incorporate antioxidant effects without losing affinity and selectivity at HDAC6. Structure-activity relationships led to compound as a hybrid molecule showing pronounced and selective inhibition of HDAC6 (IC50 = 30.7 nM, > 25-fold selectivity over other subtypes). This compound shows comparable DPPH radical scavenging ability to ferulic acid, comparable ORAC value to melatonin and comparable Cu chelating ability to EDTA. It also lacks neurotoxicity on HT-22 cells, exhibits a pronounced immunomodulatory effect, and is active in vivo showing significantly higher efficacy in an AD mouse model to prevent both Aβ25-35-induced spatial working and long-term memory dysfunction at lower dose (0.3 mg/kg) compared to positive control HDAC6 inhibitor ACY1215 and an equimolar mixture of the three entities ACY1215, melatonin and ferulic acid, suggesting potentially disease-modifying properties.
将褪黑素和阿魏酸的结构融合到基于叔胺的组蛋白去乙酰化酶 6（HDAC6）抑制剂中，开发用于神经退行性疾病的多靶标导向抑制剂，将抗氧化作用与对 HDAC6 的亲和力和选择性结合起来，而不失亲和力和选择性。构效关系导致化合物 [化合物名称] 作为一种杂合分子，对 HDAC6 表现出明显的选择性抑制作用（IC50 = 30.7 nM，对其他亚型的选择性超过 25 倍）。该化合物具有与阿魏酸相当的 DPPH 自由基清除能力、与褪黑素相当的 ORAC 值和与 EDTA 相当的铜螯合能力。它也缺乏对 HT-22 细胞的神经毒性，表现出明显的免疫调节作用，并且在体内具有活性，在 AD 小鼠模型中显示出更高的疗效，能够预防 Aβ25-35 诱导的空间工作和长期记忆功能障碍，在较低剂量（0.3 mg/kg）下与阳性对照 HDAC6 抑制剂 ACY1215 以及 ACY1215、褪黑素和阿魏酸三种物质的等摩尔混合物相比，表明具有潜在的疾病修饰特性。
