title: Synthesis, in silico docking experiments of new 2-pyrrolidinone derivatives and study of their anti-inflammatory activity.
abstract: A new class of 2-pyrrolidinone derivatives was designed, synthesized, and tested for their antioxidant and anti-inflammatory activities. The compounds were evaluated for their inhibitory activity against LOX. The most potent among them, 14d [IC(50) 0.08 (±0.005)mM], and 14e [IC(50) 0.0705 (±0.003)mM], were also tested in vivo. The compound 14d induced equipotent inhibition against rat paw edema, which is very close to the effect produced by the commonly used standard, namely indomethacin (47%). The LOX inhibitory activity of the compound 14e proceeds in parallel to the % inhibitory value of lipid peroxidation meaning that this LOX inhibitory activity is supported by the lipid peroxidation inhibition. The molecular features that govern their bioactivity were explored through in silico docking experiments. The results showed that acidic moieties must be placed in certain distance and orientation in the active site of LOX enzyme in order to productively exhibit inhibitory activity. In addition, the 2-pyrrolidinone template significantly contributes in the inhibitory properties of the new compounds.
authors.affiliation: Laboratory of Organic Chemistry, Department of Chemistry, University of Athens, Panepistimiopolis, Athens 15771, Greece. pminakak@chem.uoa.gr
authors.forename: Panagiota
authors.initials: P
authors.lastname: Moutevelis-Minakakis
authors.forename: Eleni
authors.initials: E
authors.lastname: Papavassilopoulou
authors.forename: George
authors.initials: G
authors.lastname: Michas
authors.forename: Kalliopi
authors.initials: K
authors.lastname: Georgikopoulou
authors.forename: Maria-Eleni
authors.initials: ME
authors.lastname: Ragoussi
authors.forename: Niki
authors.initials: N
authors.lastname: Neophytou
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Zoumpoulakis
authors.forename: Thomas
authors.initials: T
authors.lastname: Mavromoustakos
authors.forename: Dimitra
authors.initials: D
authors.lastname: Hadjipavlou-Litina
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D001665:Binding Sites; D020134:Catalytic Domain; D003198:Computer Simulation; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D058945:Lipoxygenases / Q000737:chemistry / Q000378:metabolism; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D011760:Pyrrolidinones / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats
chemical_list: C560332:1-((2S)-1-(4-(methoxycarbonyl)benzyl)-5-oxotetrahydro-1H-pyrrol-2-ylmethyl)-1H-imidazole-5-carboxylic acid; C560333:4-((2S)-2-(1H-imidazol-1-ylmethyl)-5-oxotetrahydro-1H-pyrrol-1-yl)methylbenzenecarboxylic acid; D000893:Anti-Inflammatory Agents; D007093:Imidazoles; D011758:Pyrroles; D011760:Pyrrolidinones; D058945:Lipoxygenases; C028537:2-pyrrolidone