Design, synthesis, biological evaluation and molecular modelling studies of conophylline inspired novel indolyl oxoacetamides as potent pancreatic lipase inhibitors
| Autor: | Atish T. Paul, Saksham Palawat, S. N. C. Sridhar |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0303 health sciences
Natural product biology 010405 organic chemistry Stereochemistry Active site General Chemistry Ligand (biochemistry) 01 natural sciences Catalysis In vitro 0104 chemical sciences 03 medical and health sciences chemistry.chemical_compound Orlistat Non-competitive inhibition chemistry Materials Chemistry biology.protein medicine IC50 Carcinogen 030304 developmental biology medicine.drug |
| Zdroj: | New Journal of Chemistry. 44:12355-12369 |
| ISSN: | 1369-9261 1144-0546 |
| Popis: | A novel series of 21 indolyl oxoacetamide analogues was designed based on the natural product lead conophylline, and evaluated for their pancreatic lipase inhibitory activity using porcine pancreatic lipase (Type II). Analogues 12c and 12b exhibited comparatively greater potential (IC50 values of 2.95 and 3.26 μM) than conophylline (IC50 – 3.31 μM), while the standard drug, orlistat, exhibited a potent IC50 value of 0.99 μM. Further, analogues 12b and 12c exhibited reversible competitive inhibition similar to orlistat and conophylline, and possessed Ki values of 1.89 and 1.69 μM, respectively. Molecular docking of these analogues was in agreement with the in vitro results, wherein the MolDock scores exhibited significant correlation with their inhibitory activity. A 10 ns molecular dynamics simulation of 12c complexed with pancreatic lipase confirmed the role of extended alkyl interactions, along with π–π stacking and π–cation interactions, in stabilising the ligand in the active site (maximum observed RMSD ≈ 3.5 A). ADMET prediction indicated the GI absorption of these analogues to be high; however, they did not possess carcinogenicity and hepatotoxicity in contrast to orlistat and conophylline. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|