Fishing Anti-Inflammatories from Known Drugs: In Silico Repurposing, Design, Synthesis and Biological Evaluation of Bisacodyl Analogues

Author(s): Maité Sylla-Iyarreta Veitía* , 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 .

Journal Name: Current Topics in Medicinal Chemistry

Volume 17 , Issue 25 , 2017

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Graphical 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.

Keywords: TOMOCOMD-CARDD Software, Atom-based bilinear indices, Anti-inflammatory database, Bisacodyl, Repurposing, Diarylmethylpyridines, Anti-inflammatory assay.

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Article Details

Year: 2017
Page: [2866 - 2887]
Pages: 22
DOI: 10.2174/1568026617666170817161953
Price: $58

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