Sulfonamido-derivatives of unsubstituted carbazoles as BACE1 inhibitors

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:27

Article

Bertini, Simone¹  Ghilardi, Elisa¹  Asso, Valentina¹  Minutolo, Filippo¹  Rapposelli, Simona¹  Digiacomo, Maria¹  Saccomanni, Giuseppe¹  Salmaso, Veronica²  Sturlese, Mattia²  Moro, Stefano²  Macchia, Marco¹  Manera, Clementina¹ 

[1] Univ Pisa, Dipartimento Farm, Via Bonanno 6, I-56126 Pisa, Italy

[2] Univ Padua, MMS, Dipartimento Sci Farmaco, Via Marzolo 5, I-35131 Padua, Italy

关键词: Alzheimer;    BACE1;    Carbazole;    Sulfonamides;    Molecular docking;   

DOI  :  10.1016/j.bmcl.2017.09.058

来源: Elsevier

【 摘 要 】

A novel series of variously substituted N-[3-(9H-carbazol-9-yl)-2-hydroxypropyl]-arylsulfonamides has been synthesized and assayed for beta-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 sub-stituents on the nitrogen atom of the arylsulfonamide moiety has so far led to the best results, with three derivatives showing IC50 values ranging from 1.6 to 1.9 mu M. Therefore, a significant improvement over the previously reported series of N-carboxamides (displaying IC50's >= 2.5 mu M) 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. (C) 2017 Elsevier Ltd. All rights reserved.

【 授权许可】

Free