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

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.Dany Siverio-Mota acknowledges the Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven (Belgium) for kind hospitality and VLIR (Vlaamse InterUniversitaire Raad, Flemish Interuniversity Council, Belgium) under the IUC Program VLIR-UCLV for in part financial support of this work. Yovani Marrero Ponce thanks the program ‘Estades Temporals per a Investigadors Convidats’ for a fellowship to work at Universitat de València, Spain. The spanish Ministry of Science and Innovation (project SAF2009- 10399) and LabEx LERMIT (ANR-10-LABX-33) are also acknowlwdged for the financial supportPeer Reviewe