PUBLICATION
Fishing Anti-Inflammatories from Known Drugs: In Silico Repurposing, Design, Synthesis and Biological Evaluation of Bisacodyl Analogues
- Authors
- Veitía, M.S., Mota, D.S., Lerari, V., Marín, M., Giner, R.M., Muro, L.V., Guerra, Y.R., Dumas, F., Ferroud, C., de Witte, P.A.M., Crawford, A.D., Arán, V.J., Ponce, Y.M.
- ID
- ZDB-PUB-170818-7
- Date
- 2017
- Source
- Current topics in medicinal chemistry : (Journal)
- Registered Authors
- Crawford, Alexander
- Keywords
- Anti-inflammatory assay, Anti-inflammatory database, Atom-based bilinear indices, Bisacodyl, Diarylmethylpyridines, Repurposing, TOMOCOMD-CARDD Software
- MeSH Terms
- none
- PubMed
- 28816107 Full text @ Curr. Top. Med. Chem.
Citation
Veitía, M.S., Mota, D.S., Lerari, V., Marín, M., Giner, R.M., Muro, L.V., Guerra, Y.R., Dumas, F., Ferroud, C., de Witte, P.A.M., Crawford, A.D., Arán, V.J., Ponce, Y.M. (2017) Fishing Anti-Inflammatories from Known Drugs: In Silico Repurposing, Design, Synthesis and Biological Evaluation of Bisacodyl Analogues. Current topics in medicinal chemistry. .
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping