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

[ Vol. 17 , Issue. 25 ]

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 and Yovani Marrero Ponce   Pages 2866 - 2887 ( 22 )

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.

Affiliation:

Equipe de chimie moléculaire, Laboratoire Chimie Moléculaire, génie des procédés chimiques et énergétiques (CMGPCE), EA 7341- Conservatoire National des Arts et Métiers, 2 rue Conté, 75003, Paris, Unit of Computer- Aided Molecular “Biosilico” Discovery and Bioinformatic Research (CAMD-BIR Unit), Faculty of Chemistry- Pharmacy, Universidad Central “Marta Abreu” de Las Villas, Santa Clara, 54830, Villa Clara, Equipe de chimie moléculaire, Laboratoire Chimie Moléculaire, génie des procédés chimiques et énergétiques (CMGPCE), EA 7341- Conservatoire National des Arts et Métiers, 2 rue Conté, 75003, Paris, Department of Pharmacology, Faculty of Pharmacy, Universitat de València, València, Department of Pharmacology, Faculty of Pharmacy, Universitat de València, València, Unit of Computer- Aided Molecular “Biosilico” Discovery and Bioinformatic Research (CAMD-BIR Unit), Faculty of Chemistry- Pharmacy, Universidad Central “Marta Abreu” de Las Villas, Santa Clara, 54830, Villa Clara, Unit of Computer- Aided Molecular “Biosilico” Discovery and Bioinformatic Research (CAMD-BIR Unit), Faculty of Chemistry- Pharmacy, Universidad Central “Marta Abreu” de Las Villas, Santa Clara, 54830, Villa Clara, Laboratoire BioCIS, CNRS UMR 8076, IPSIT, Faculté de Pharmacie, Université Paris Sud, Université Paris Saclay, 92296 Châtenay-Malabry Cedex, Equipe de chimie moléculaire, Laboratoire Chimie Moléculaire, génie des procédés chimiques et énergétiques (CMGPCE), EA 7341- Conservatoire National des Arts et Métiers, 2 rue Conté, 75003, Paris, Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, Herestraat 49, 3000 Leuven, Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, Herestraat 49, 3000 Leuven, Instituto de Química Médica, CSIC, c/Juan de la Cierva 3, 28006 Madrid, Grupo de Investigación Ambiental (GIA), Programas Ambientales, Facultad de Ingenierías, Fundación Universitaria Tecnológico de Comfenalco (COMFENALCO), Cartagena de Indias, Bolívar

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