Synthesis and in vitro evaluation of anti-inflammatory, antioxidant, and anti-fibrotic effects of new 8-aminopurine-2,6-dione-based phosphodiesterase inhibitors as promising anti-asthmatic agents

Katarzyna Wójcik-Pszczoła*, Agnieszka Jankowska, Marietta Ślusarczyk, Bogdan Jakieła, Hanna Plutecka, Krzysztof Pociecha, Artur Świerczek, Justyna Popiół, Paulina Koczurkiewicz-Adamczyk, Elżbieta Wyska, Elżbieta Pękala, Reinoud Gosens, Grażyna Chłoń-Rzepa

*Corresponding author for this work

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Abstract

Phosphodiesterase (PDE) inhibitors are currently an extensively studied group of compounds that can bring many benefits in the treatment of various inflammatory and fibrotic diseases, including asthma. Herein, we describe a series of novel N’-phenyl- or N’-benzylbutanamide and N’-arylidenebutanehydrazide derivatives of 8-aminopurine-2,6-dione (27–43) and characterized them as prominent pan-PDE inhibitors. Most of the compounds exhibited antioxidant and anti-inflammatory activity in lipopolysaccharide (LPS)-induced murine macrophages RAW264.7. The most active compounds (32–35 and 38) were evaluated in human bronchial epithelial cells (HBECs) derived from asthmatics. To better map the bronchial microenvironment in asthma, HBECs after exposure to selected 8-aminopurine-2,6-dione derivatives were incubated in the presence of two proinflammatory and/or profibrotic factors: transforming growth factor type β (TGF-β) and interleukin 13 (IL-13). Compounds 32–35 and 38 significantly reduced both IL-13- and TGF-β-induced expression of proinflammatory and profibrotic mediators, respectively. Detailed analysis of their inhibition preferences for selected PDEs showed high affinity for isoenzymes important in the pathogenesis of asthma, including PDE1, PDE3, PDE4, PDE7, and PDE8. The presented data confirm that structural modifications within the 7 and 8 positions of the purine-2,6-dione core result in obtaining preferable pan-PDE inhibitors which in turn exert an excellent anti-inflammatory and anti-fibrotic effect in the bronchial epithelial cells derived from asthmatic patients. This dual-acting pan-PDE inhibitors constitute interesting and promising lead structures for further anti-asthmatic agent discovery.

Original languageEnglish
Article number105409
Number of pages17
JournalBioorganic Chemistry
Volume117
Early online date16-Oct-2021
DOIs
Publication statusPublished - Dec-2021

Keywords

  • Airway inflammation
  • Airway remodeling
  • Asthma
  • Bronchial epithelium
  • Phosphodiesterase inhibitors
  • Theophylline

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