Laboratorio de Radicales Libres y Química Computacional (IQOG, CSIC), C/Juan de la Cierva 3, 28006 Madrid, Spain.
Bioorg Med Chem. 2011 Jan 1;19(1):122-33. doi: 10.1016/j.bmc.2010.11.040. Epub 2010 Nov 26.
The synthesis, biological assessment, and molecular modelling of new tacrine analogues 11-22 is described. Compounds 11-22 have been obtained by Friedländer-type reaction of 2-aminopyridine-3-carbonitriles 1-10 with cyclohexanone or 1-benzyl-4-piperidone. The biological evaluation showed that some of these molecules were good AChE inhibitors, in the nanomolar range, and quite selective regarding the inhibition of BuChE, the most potent being 5-amino-2-(dimethylamino)-6,7,8,9-tetrahydrobenzo[1,8-b]-naphthyridine-3-carbonitrile (11) [IC(50) (EeAChE: 14nM); IC(50) (eqBuChE: 5.2μM]. Kinetic studies on the easily available and potent anticholinesterasic compound 5-amino-2-(methoxy)-6,7,8,9-tetrahydrobenzo[1,8-b]-naphthyridine-3-carbonitrile (16) [IC(50) (EeAChE: 64nM); IC(50) (eqBuChE: 9.6μM] showed that this compound is a mixed-type inhibitor (K(i)=69.2nM) of EeAChE. Molecular modelling on inhibitor 16 confirms that this compound, as expected and similarly to tacrine, binds at the catalytic active site of EeAChE. The neuroprotective profile of molecules 11-22 has been investigated in SH-SY5Y neuroblastoma cells stressed with a mixture of oligomycin-A/rotenone. Compound 16 was also able to rescue by 50% cell death induced by okadaic acid in SH-SY5Y cells. From these results we conclude that the neuroprotective profile of these molecules is moderate, the most potent being compounds 12 and 17 which reduced cell death by 29%. Compound 16 does not affect ACh- nor K(+)-induced calcium signals in bovine chromaffin cells. Consequently, tacrine analogues 11-22 can be considered attractive therapeutic molecules on two key pharmacological targets playing key roles in the progression of Alzheimer, that is, cholinergic dysfunction and oxidative stress, as well as in neuronal cerebrovascular diseases.
描述了新型他克林类似物 11-22 的合成、生物评估和分子建模。通过 2-氨基吡啶-3-氰化物 1-10 与环己酮或 1-苄基-4-哌啶酮的 Friedländer 型反应得到化合物 11-22。生物评价表明，这些分子中的一些是良好的 AChE 抑制剂，在纳摩尔范围内，对 BuChE 的抑制具有相当的选择性，最有效的是 5-氨基-2-(二甲基氨基)-6,7,8,9-四氢苯并[1,8-b]-萘啶-3-甲腈 (11) [IC(50)(EeAChE: 14nM); IC(50)(eqBuChE: 5.2μM]。对易于获得且有效的抗胆碱酯酶化合物 5-氨基-2-(甲氧基)-6,7,8,9-四氢苯并[1,8-b]-萘啶-3-甲腈 (16) [IC(50)(EeAChE: 64nM); IC(50)(eqBuChE: 9.6μM]的动力学研究表明，该化合物是 EeAChE 的混合型抑制剂 (K(i)=69.2nM)。抑制剂 16 的分子建模证实，该化合物与他克林一样，结合在 EeAChE 的催化活性部位。在寡霉素 A/鱼藤酮混合物应激的 SH-SY5Y 神经母细胞瘤细胞中，研究了 11-22 种分子的神经保护谱。化合物 16 还能够挽救由 SH-SY5Y 细胞中 okadaic 酸诱导的 50%细胞死亡。从这些结果中，我们得出结论，这些分子的神经保护谱是适度的，最有效的是化合物 12 和 17，它们将细胞死亡减少了 29%。化合物 16 不影响牛嗜铬细胞瘤细胞中 ACh-或 K(+)-诱导的钙信号。因此，他克林类似物 11-22 可被视为在两个关键的药理靶点上具有吸引力的治疗分子，这两个靶点在阿尔茨海默病的进展中起着关键作用，即胆碱能功能障碍和氧化应激，以及神经元脑血管疾病。
