Fishing anti-inflammatories from known drugs: In silico repurposing, design, synthesis and biological evaluation of bisacodyl analogues
| Autor: | Yovani Marrero Ponce, Françoise Dumas, Rosa M. Giner, Peter de Witte, Vicente J. Arán, Clotilde Ferroud, Yankier Rivero Guerra, Maité Sylla-Iyarreta Veitía, Liliana Vicet Muro, Vanessa Lerari, Marta Marín, Dany Siverio Mota, Alexander D. Crawford |
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| Přispěvatelé: | Ministerio de Economía, Industria y Competitividad (España), Laboratoire de Chimie moléculaire, génie des procédés chimiques et énergétiques (CMGPCE), Conservatoire National des Arts et Métiers [CNAM] (CNAM), Universidad Central Marta Abreu de Las Villas [Cuba] (UCLV), Universitat de València (UV), Biomolécules : Conception, Isolement, Synthèse (BioCIS), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-CY Cergy Paris Université (CY), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Instituto de Quimica Médica (CSIC), Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Fundación Universitaria Tecnológico de Comfenalco |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Drug Bisacodyl Anti-inflammatory database media_common.quotation_subject In silico [CHIM.THER]Chemical Sciences/Medicinal Chemistry 03 medical and health sciences In vivo Molecular descriptor Drug Discovery Diarylmethylpyridines medicine [CHIM.CRIS]Chemical Sciences/Cristallography Repurposing ComputingMilieux_MISCELLANEOUS media_common Anti-inflammatory assay Chemistry [CHIM.ORGA]Chemical Sciences/Organic chemistry General Medicine Combinatorial chemistry [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM] 3. Good health 030104 developmental biology Mechanism of action Atom-based bilinear indices medicine.symptom Pharmacophore TOMOCOMD-CARDD Software medicine.drug |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname Current Topics in Medicinal Chemistry Current Topics in Medicinal Chemistry, Bentham Science Publishers, 2017, 17 (25), ⟨10.2174/1568026617666170817161953⟩ |
| ISSN: | 1568-0266 |
| DOI: | 10.2174/1568026617666170817161953⟩ |
| Popis: | 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 support |
| Databáze: | OpenAIRE |
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