New α-Hydroxy-1,2,3-triazoles and 9H-Fluorenes-1,2,3-triazoles: Synthesis and Evaluation as Glycine Transporter 1 Inhibitors

Two series of new compounds containing 1,2,3-triazole moiety were designed as putative GlyT1 inhibitors aiming the discovery of new hits with activity in cognitive disorders. 1,4-Disubstituted α-hydroxy-1,2,3-triazoles were obtained as racemates in moderate to good yields by the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction (click chemistry) as the key step between propargyl alcohols and aryl azides, previously prepared from anilines or boronic acids. Benzo[c]chromene-triazoles were planned to be obtained by palladium-catalyzed C−H activation using [bis(trifluoroacetoxy)iodobenzene] (PhI(TFA)2) of some α-hydroxy-1,2,3-triazoles, since benzo[c]chromenes are also privileged groups with several biological activities, including to the central nervous system. Unexpectedly, 9H-fluorenes-1,2,3-triazoles, instead of benzo[c]chromene-triazoles, were obtained by Friedel-Crafts alkylation reaction. The two series of compounds were tested for inhibition of the glycine transporter (rat GlyT1 isoform) but only the α-hydroxy-1,2,3-triazole 9b was active (half maximal inhibitory concentration (IC50) = 8.0 µM).

设计了两类含1,2,3-三唑(1,2,3-triazole)基团的新型化合物，作为潜在的甘氨酸转运蛋白1（GlyT1）抑制剂，旨在发现可用于治疗认知障碍的活性苗头化合物。1,4-二取代-α-羟基-1,2,3-三唑以消旋体形式得到，收率中等至良好，其关键合成步骤为铜催化叠氮-炔环加成（CuAAC，点击化学）反应，以炔丙醇与芳基叠氮为底物；芳基叠氮此前可由苯胺或硼酸制备得到。原计划通过钯催化C−H活化反应，利用[双(三氟乙酰氧基)碘苯](PhI(TFA)₂)对部分α-羟基-1,2,3-三唑进行修饰，以合成苯并[c]色烯-三唑类化合物；鉴于苯并[c]色烯本身也是一类具有多种生物活性（包括中枢神经系统相关活性）的优势骨架。但意外的是，最终通过傅克烷基化反应得到的并非苯并[c]色烯-三唑，而是9H-芴-1,2,3-三唑类化合物。对这两类化合物开展了甘氨酸转运蛋白（大鼠GlyT1亚型）抑制活性测试，仅α-羟基-1,2,3-三唑9b表现出抑制活性，其半数抑制浓度（IC₅₀）为8.0 μM。