1H-pyrrolo[2,3-b]pyridine: A new scaffold for human neutrophil elastase (HNE) inhibitors

Letizia Crocetti, Maria Paola Giovannoni, Igor A. Schepetkin, Mark T. Quinn, Andrei I. Khlebnikov, Niccolò Cantini, Gabriella Guerrini, Antonella Iacovone, Elisabetta Teodori, Claudia Vergelli

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4 Citations (Scopus)


Human neutrophil elastase (HNE) is a potent serine protease belonging to the chymotrypsin family. It is an important target for the development of novel and selective inhibitors for the treatment of inflammatory diseases, especially pulmonary pathologies. Here, we report the synthesis and biological evaluation of a new series of HNE inhibitors with a pyrrolo[2,3-b]pyridine scaffold, which is an isomer of our previously reported indazoles, in order to assess how a shift of the nitrogen from position 2 to position 7 influences activity. The majority of new compounds were effective HNE inhibitors and had IC50 values in the micromolar/submicromolar range, with some compounds active in low nanomolar levels. For example, 2a and 2b inhibited HNE with IC50 values of 15 and 14 nM, respectively. Molecular modeling of compounds differing in the position of heteroatom(s) in the bicyclic moiety and in the oxadiazole ring demonstrated that the calculated geometries of enzyme-inhibitor complexes were in agreement with the observed biological activities. Docking experiments showed that orientation of the active pyrrolo[2,3-b]pyridines in the HNE catalytic triad Ser195-His57-Asp102 correlated with effectiveness of the inhibitor interaction with the enzyme. Thus, the pyrrolo[2,3-b]pyridine scaffold represents a novel scaffold for the development of potent HNE inhibitors.

Original languageEnglish
Pages (from-to)5583-5595
Number of pages13
JournalBioorganic and Medicinal Chemistry
Issue number21
Publication statusPublished - 15 Nov 2018


  • Human neutrophil elastase
  • Inhibitor
  • Molecular docking
  • Pyrrolo[2,3-b]pyridine

ASJC Scopus subject areas

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

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  • Cite this

    Crocetti, L., Giovannoni, M. P., Schepetkin, I. A., Quinn, M. T., Khlebnikov, A. I., Cantini, N., Guerrini, G., Iacovone, A., Teodori, E., & Vergelli, C. (2018). 1H-pyrrolo[2,3-b]pyridine: A new scaffold for human neutrophil elastase (HNE) inhibitors. Bioorganic and Medicinal Chemistry, 26(21), 5583-5595. https://doi.org/10.1016/j.bmc.2018.09.034