Bertini Simone, Ghilardi Elisa, Asso Valentina, Minutolo Filippo, Rapposelli Simona, Digiacomo Maria, Saccomanni Giuseppe, Salmaso Veronica, Sturlese Mattia, Moro Stefano, Macchia Marco, Manera Clementina
Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
Bioorg Med Chem Lett. 2017 Nov 1;27(21):4812-4816. doi: 10.1016/j.bmcl.2017.09.058. Epub 2017 Sep 28.
A novel series of variously substituted N-[3-(9H-carbazol-9-yl)-2-hydroxypropyl]-arylsulfonamides has been synthesized and assayed for β-Secretase (BACE1) inhibitory activity. BACE1 is a widely recognized drug target for the prevention and treatment of Alzheimer's Disease (AD). The introduction of benzyl substituents on the nitrogen atom of the arylsulfonamide moiety has so far led to the best results, with three derivatives showing IC values ranging from 1.6 to 1.9 μM. Therefore, a significant improvement over the previously reported series of N-carboxamides (displaying IC's ≥ 2.5 μM) has been achieved, thus suggesting an active role of the sulfonamido-portion in the inhibition process. Preliminary molecular modeling studies have been carried out to rationalize the observed structure-activity relationships.
合成了一系列新型的不同取代的N-[3-(9H-咔唑-9-基)-2-羟丙基]-芳基磺酰胺，并对其进行了β-分泌酶（BACE1）抑制活性测定。BACE1是预防和治疗阿尔茨海默病（AD）的一个广泛认可的药物靶点。迄今为止，在芳基磺酰胺部分的氮原子上引入苄基取代基已产生了最佳结果，有三种衍生物的IC值在1.6至1.9μM范围内。因此，相对于先前报道的N-羧酰胺系列（IC值≥2.5μM）有了显著改进，这表明磺酰胺部分在抑制过程中发挥了积极作用。已进行了初步的分子模拟研究，以合理化观察到的构效关系。
