Design, synthesis and evaluation of N-benzoylindazole derivatives and analogues as inhibitors of human neutrophil elastase

Letizia Crocetti, Maria Paola Giovannoni, Igor A. Schepetkin, Mark T. Quinn, Andrey Ivanovich Khlebnikov, Agostino Cilibrizzi, Vittorio Dal Piaz, Alessia Graziano, Claudia Vergelli

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Human neutrophil elastase (HNE) plays an important role in tumour invasion and inflammation. A series of N-benzoylindazoles was synthesized and evaluated for their ability to inhibit HNE. We found that this scaffold is appropriate for HNE inhibitors and that the benzoyl fragment at position 1 is essential for activity. The most active compounds inhibited HNE activity with IC 50 values in the submicromolar range. Furthermore, docking studies indicated that the geometry of an inhibitor within the binding site and energetics of Michaelis complex formation were key factors influencing the inhibitor's biological activity. Thus, N-benzoylindazole derivatives and their analogs represent novel structural templates that can be utilized for further development of efficacious HNE inhibitors.

Original languageEnglish
Pages (from-to)4460-4472
Number of pages13
JournalBioorganic and Medicinal Chemistry
Volume19
Issue number15
DOIs
Publication statusPublished - 1 Aug 2011
Externally publishedYes

Fingerprint

Secretory Proteinase Inhibitory Proteins
Leukocyte Elastase
Derivatives
Bioactivity
Scaffolds
Aptitude
Tumors
Human Development
Binding Sites
Geometry
Inflammation
Neoplasms

Keywords

  • 1-Benzoylindazoles
  • Human neutrophil elastase
  • Indazoles
  • Inhibitors
  • Structure-activity relationship

ASJC Scopus subject areas

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

Cite this

Design, synthesis and evaluation of N-benzoylindazole derivatives and analogues as inhibitors of human neutrophil elastase. / Crocetti, Letizia; Giovannoni, Maria Paola; Schepetkin, Igor A.; Quinn, Mark T.; Khlebnikov, Andrey Ivanovich; Cilibrizzi, Agostino; Piaz, Vittorio Dal; Graziano, Alessia; Vergelli, Claudia.

In: Bioorganic and Medicinal Chemistry, Vol. 19, No. 15, 01.08.2011, p. 4460-4472.

Research output: Contribution to journalArticle

Crocetti, Letizia ; Giovannoni, Maria Paola ; Schepetkin, Igor A. ; Quinn, Mark T. ; Khlebnikov, Andrey Ivanovich ; Cilibrizzi, Agostino ; Piaz, Vittorio Dal ; Graziano, Alessia ; Vergelli, Claudia. / Design, synthesis and evaluation of N-benzoylindazole derivatives and analogues as inhibitors of human neutrophil elastase. In: Bioorganic and Medicinal Chemistry. 2011 ; Vol. 19, No. 15. pp. 4460-4472.
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