Fishing anti-inflammatories from known drugs: In silico repurposing, design, synthesis and biological evaluation of bisacodyl analogues

Maité Sylla Iyarreta Veítia, Dany Siverio Mota, Vanessa Lerari, Marta Marín, Rosa M. Giner, Liliana Vicet Muro, Yankier Rivero Guerra, Françoise Dumas, Clotilde Ferroud, Peter A.M. De Witte, Alexander D. Crawford, Vicente J. Arán, Yovani Marrero Ponce

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Herein is described in silico repositioning, design, synthesis, biological evaluation and structure-activity relationship (SAR) of an original class of anti-inflammatory agents based on a polyaromatic pharmacophore structurally related to bisacodyl (BSL) drug used in therapeutic as laxative. We describe the potential of TOMOCOMD-CARDD methods to find out new anti-inflammatory drug-like agents from a diverse series of compounds using the total and local atom based bilinear indices as molecular descriptors. The models obtained were validated by biological studies, identifying BSL as the first anti-inflammatory lead-like using in silico repurposing from commercially available drugs. Several biological in vitro and in vivo assays were performed in order to understand its mechanism of action. A set of analogues of BSL was prepared using low-cost synthetic procedures and further biologically investigated in zebrafish models. Compound 5c and 7e exhibited the best antiinflammatory activities and represent new promising anti-inflammatory agents for further preclinical development.

Original languageEnglish
Pages (from-to)2866-2887
Number of pages22
JournalCurrent Topics in Medicinal Chemistry
Volume17
Issue number25
DOIs
StatePublished - 1 Oct 2017

Keywords

  • Anti-inflammatory assay
  • Anti-inflammatory database
  • Atom-based bilinear indices
  • Bisacodyl
  • Diarylmethylpyridines
  • Repurposing
  • TOMOCOMD-CARDD software

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