Synthesis, modeling and biological evaluation of some pyrazolo[3,4-d]pyrimidinones and pyrazolo[4,3-e][1,2,4]triazolo[4,3-a]pyrimidinones as anti-inflammatory agents
| Autor: | Hayam M. A. Ashour, Tamer M. Ibrahim, Rasha A. Nassra, Mounir A. Khalil, Ibrahim M. Labouta, Salwa M. Fahmy, Gina N. Tageldin |
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| Rok vydání: | 2018 |
| Předmět: |
Diclofenac
medicine.drug_class In silico Anti-Inflammatory Agents Pyrimidinones Pharmacology 01 natural sciences Biochemistry Anti-inflammatory Structure-Activity Relationship Pharmacokinetics In vivo Drug Discovery medicine Animals Edema Rats Wistar Molecular Biology Inflammation Binding Sites Granuloma Cyclooxygenase 2 Inhibitors Molecular Structure 010405 organic chemistry Chemistry Organic Chemistry Triazoles In vitro 0104 chemical sciences Molecular Docking Simulation 010404 medicinal & biomolecular chemistry Celecoxib Cyclooxygenase 2 Pyrazoles Female Selectivity medicine.drug |
| Zdroj: | Bioorganic chemistry. 90 |
| ISSN: | 1090-2120 |
| Popis: | New pyrazolo[3,4-d]pyrimidinone and pyrazolo[4,3-e][1,2,4]triazolo[4,3-a]pyrimidinone derivatives were synthesized. They have been evaluated for their anti-inflammatory activity using in vitro (COX-1/COX-2) inhibitory assay. Moreover, compounds with promising in vitro activity and COX-1/COX-2 selectivity indices were subjected for in vivo anti-inflammatory testing using formalin induced paw edema and cotton-pellet induced granuloma assays for acute and chronic models, respectively. Compounds (2c, 3i, 6a, 8 and 12) showed promising COX-2 inhibitory activity and high selectivity compared to celecoxib. Most of the compounds exhibited potential anti-inflammatory activity for both in vivo acute and chronic models. Almost all compounds displayed safe gastrointestinal profile and low ulcerogenic potential guided by histopathological examination. Furthermore, molecular docking experiments rationalized the observed in vitro anti-inflammatory activity of selected candidates. In silico predictions of the pharmacokinetic and drug-likeness properties recommended accepted profiles of the majority of compounds. In conclusion, this work provides an extension of the chemical space of pyrazolopyrimidinone and pyrazolotriazolopyrimidinone chemotypes for the anti-inflammatory activity. |
| Databáze: | OpenAIRE |
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