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