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Sulfonamido-derivatives of unsubstituted carbazoles as BACE1 inhibitors.

Authors
  • Bertini, Simone1
  • Ghilardi, Elisa2
  • Asso, Valentina2
  • Minutolo, Filippo2
  • Rapposelli, Simona2
  • Digiacomo, Maria2
  • Saccomanni, Giuseppe2
  • Salmaso, Veronica3
  • Sturlese, Mattia3
  • Moro, Stefano3
  • Macchia, Marco2
  • Manera, Clementina2
  • 1 Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy. Electronic address: [email protected] , (Italy)
  • 2 Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy. , (Italy)
  • 3 Molecular Modeling Section (MMS), Dipartimento di Scienze del Farmaco, Università di Padova, Via Marzolo 5, I-35131 Padova, Italy. , (Italy)
Type
Published Article
Journal
Bioorganic & medicinal chemistry letters
Publication Date
Nov 01, 2017
Volume
27
Issue
21
Pages
4812–4816
Identifiers
DOI: 10.1016/j.bmcl.2017.09.058
PMID: 28993050
Source
Medline
Keywords
License
Unknown

Abstract

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 IC50 values ranging from 1.6 to 1.9 μM. Therefore, a significant improvement over the previously reported series of N-carboxamides (displaying IC50'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.

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