Substituted pyrazolones require N2 hydrogen bond donating ability to protect against cytotoxicity from protein aggregation of mutant superoxide dismutase 1

Paul C. Trippier, Radhia Benmohammed, Donald R. Kirsch, Richard B. Silverman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Amyotrophic lateral sclerosis (ALS) is a debilitating and fatal neurodegenerative disease. Although the cause remains unknown, misfolded protein aggregates are seen in neurons of sporadic ALS patients, and familial ALS mutations, including mutations in superoxide dismutase 1 (SOD1), produce proteins with an increased propensity to misfold and aggregate. A structure activity relationship of a lead scaffold exhibiting neuroprotective activity in a G93A-SOD1 mouse model for ALS has been further investigated in a model PC12 cellular assay. Synthesis of biotinylated probes at the N1 nitrogen of the pyrazolone ring gave compounds (5d-e) that retained activity within 10-fold of the proton-bearing lead compound (5a) and were equipotent with a sterically less cumbersome N1-methyl substituted analogue (5b). However, when methyl substitution was introduced at N1 and N 2 of the pyrazolone ring, the compound was inactive (5c). These data led us to investigate further the pharmacophoric nature of the pyrazolone unit. A range of N1 substitutions were tolerated, leading to the identification of an N1-benzyl substituted pyrazolone (5m), equipotent with 5a. Substitution at N2 or excision of N2, however, removed all activity. Therefore, the hydrogen bond donating ability of the N2-H of the pyrazolone ring appears to be a critical part of the structure, which will influence further analogue synthesis.

Original languageEnglish (US)
Pages (from-to)6647-6650
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume22
Issue number21
DOIs
StatePublished - Nov 1 2012

Keywords

  • Amyotrophic lateral sclerosis
  • Neuroprotection
  • Pharmacophore
  • Pyrazolone
  • Superoxide dismutase 1

ASJC Scopus subject areas

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

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