title: Design, synthesis, and local anti-inflammatory activity of 17β-carboxamide derivatives of glucocorticoids.
abstract: Molecular docking studies were performed on 18 17β-carboxamide steroids in order to select compounds with potential local anti-inflammatory activity. These derivatives are amides of cortienic acids (obtained from hydrocortisone, prednisolone, and methylprednisolone) with methyl or ethyl esters of six amino acids. Interactions with the glucocorticoid receptor (GR), binding energies and ligand efficiency values of these compounds were compared with dexamethasone and cortienic acid obtained from prednisolone (inactive metabolite). On the basis of molecular docking studies, seven compounds were selected and their binding affinities for the GR were predicted by use of the exponential model created in this study. Subsequently, selected compounds were synthesized in good yields by use of modified N,N'-dicyclohexylcarbodiimide (DCC)/1-hydroxybenzotriazole (HOBt) coupling procedure. Finally, the local anti-inflammatory activity of the synthesized compounds was examined by use of the croton oil-induced ear edema test. In vivo evaluation of systemic side effects as well as in silico prediction of metabolism were performed on the derivative with the best local anti-inflammatory activity. The combination of molecular docking studies and the exponential model for the GR binding affinity prediction could be used as an in silico tool for the rational design of novel 17β-carboxamide steroids with potentially better biological profile than dexamethasone.
authors.affiliation: Faculty of Pharmacy, Department of Pharmaceutical Chemistry, University of Belgrade, Belgrade, Serbia.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Dobričić
authors.forename: Bojan
authors.initials: B
authors.lastname: Marković
authors.forename: Nikola
authors.initials: N
authors.lastname: Milenković
authors.forename: Vladimir
authors.initials: V
authors.lastname: Savić
authors.forename: Vesna
authors.initials: V
authors.lastname: Jaćević
authors.forename: Nemanja
authors.initials: N
authors.lastname: Rančić
authors.forename: Sote
authors.initials: S
authors.lastname: Vladimirov
authors.forename: Olivera
authors.initials: O
authors.lastname: Cudina
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D001711:Biotransformation; D003436:Croton Oil; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control*; D005938:Glucocorticoids / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D006854:Hydrocortisone / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D007249:Inflammation / Q000139:chemically induced / Q000517:prevention & control*; D008024:Ligands; D008775:Methylprednisolone / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D008954:Models, Biological; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011239:Prednisolone / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D008024:Ligands; D011965:Receptors, Glucocorticoid; D003436:Croton Oil; D011239:Prednisolone; D006854:Hydrocortisone; D008775:Methylprednisolone
keywords: 17β-Carboxamide steroids; Glucocorticoid receptor binding affinity; Local anti-inflammatory activity; Molecular docking studies; Systemic side effects