Sulfonamides as multifunctional agents for Alzheimer's disease

Seema Bag; Rekha Tulsan; Abha Sood; Hyejin Cho; Hana Redjeb; Weihong Zhou; Harry LeVine 3rd; Béla Török; Marianna Török

doi:10.1016/j.bmcl.2014.12.006

Sulfonamides as multifunctional agents for Alzheimer's disease

Bioorg Med Chem Lett. 2015 Feb 1;25(3):626-30. doi: 10.1016/j.bmcl.2014.12.006. Epub 2014 Dec 9.

Authors

Seema Bag¹, Rekha Tulsan¹, Abha Sood¹, Hyejin Cho¹, Hana Redjeb¹, Weihong Zhou¹, Harry LeVine 3rd², Béla Török³, Marianna Török⁴

Affiliations

¹ Department of Chemistry, University of Massachusetts Boston, 100 Morrissey Blvd., Boston, MA, USA.
² Department of Molecular and Cellular Biochemistry, Chandler School of Medicine, and Center on Aging, University of Kentucky, Lexington, KY 40536, USA.
³ Department of Chemistry, University of Massachusetts Boston, 100 Morrissey Blvd., Boston, MA, USA. Electronic address: bela.torok@umb.edu.
⁴ Department of Chemistry, University of Massachusetts Boston, 100 Morrissey Blvd., Boston, MA, USA. Electronic address: marianna.torok@umb.edu.

PMID: 25537270
DOI: 10.1016/j.bmcl.2014.12.006

Abstract

Sulfonamide linker-based inhibitors with extended linear structure were designed and synthesized with the aim of producing multifunctional agents against several processes involved in the pathology of Alzheimer's disease (AD). The potency of the compounds were assessed in the inhibition of Aβ self-assembly (fibril and oligomer formation), in modulating cholinesterase (AChE, BuChE) activity, and scavenging free radicals. Several compounds exhibited promising Aβ self-assembly and cholinesterase inhibition and in parallel, showed good free radical scavenging properties. The investigation of the scaffold described in this study resulted in the identification of three compounds (14, 19 and 26) as promising leads for the further design of multifunctional drug candidates for AD.

Keywords: Alzheimer’s disease; Amyloid-β; Antioxidant; Cholinesterase inhibition; Sulfonamides.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylcholinesterase / chemistry
Acetylcholinesterase / metabolism
Alzheimer Disease / drug therapy
Amyloid beta-Peptides / antagonists & inhibitors
Amyloid beta-Peptides / metabolism
Binding Sites
Butyrylcholinesterase / chemistry
Butyrylcholinesterase / metabolism
Catalytic Domain
Cholinesterase Inhibitors / chemistry*
Cholinesterase Inhibitors / metabolism
Cholinesterase Inhibitors / therapeutic use
Donepezil
Free Radical Scavengers / chemistry*
Free Radical Scavengers / metabolism
Free Radical Scavengers / therapeutic use
Humans
Indans / chemistry
Indans / metabolism
Molecular Dynamics Simulation
Piperidines / chemistry
Piperidines / metabolism
Protein Binding
Sulfonamides / chemistry*
Sulfonamides / metabolism
Sulfonamides / therapeutic use

Substances

Amyloid beta-Peptides
Cholinesterase Inhibitors
Free Radical Scavengers
Indans
Piperidines
Sulfonamides
Donepezil
Acetylcholinesterase
Butyrylcholinesterase