3-(N-Arylsulfamoyl)benzamides, inhibitors of human sirtuin type 2 (SIRT2)

Soo Hyuk Choi, Luisa Quinti, Aleksey G. Kazantsev, Richard B. Silverman

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Inhibition of sirtuin 2 (SIRT2) is known to be protective against the toxicity of disease proteins in Parkinson's and Huntington's models of neurodegeneration. Previously, we developed SIRT2 inhibitors based on the 3-(N-arylsulfamoyl)benzamide scaffold, including3-(N-(4-bromophenyl)sulfamoyl)- N-(4-bromophenyl)benzamide(C2-8, 1a), which demonstrated neuroprotective effects in a Huntington's mouse model, but had low potency of SIRT2 inhibition. Here we report that N-methylation of 1a greatly increases its potency and results in excellent selectivity for SIRT2 over SIRT1 and SIRT3 isoforms. Structure-activity relationships observed for 1a analogs and docking simulation data suggest that the para-substituted amido moiety of these compounds could occupy two potential hydrophobic binding pockets in SIRT2. These results provide a direction for the design of potent drug-like SIRT2 inhibitors.

Original languageEnglish
Pages (from-to)2789-2793
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume22
Issue number8
DOIs
Publication statusPublished - 2012 Apr 15

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Sirtuin 2
Benzamides
Methylation
Drug Design
Neuroprotective Agents
Structure-Activity Relationship
Scaffolds
Toxicity
Protein Isoforms

All Science Journal Classification (ASJC) codes

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

Cite this

Choi, Soo Hyuk ; Quinti, Luisa ; Kazantsev, Aleksey G. ; Silverman, Richard B. / 3-(N-Arylsulfamoyl)benzamides, inhibitors of human sirtuin type 2 (SIRT2). In: Bioorganic and Medicinal Chemistry Letters. 2012 ; Vol. 22, No. 8. pp. 2789-2793.
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3-(N-Arylsulfamoyl)benzamides, inhibitors of human sirtuin type 2 (SIRT2). / Choi, Soo Hyuk; Quinti, Luisa; Kazantsev, Aleksey G.; Silverman, Richard B.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 22, No. 8, 15.04.2012, p. 2789-2793.

Research output: Contribution to journalArticle

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