title: Marginally designed new profen analogues have the potential to inhibit cyclooxygenase enzymes.
abstract: The current structure-activity relationship of profens (i.e., 2-arylpropionic acid derivatives, a class of non-steroidal anti-inflammatory drugs) discusses the importance of α-monomethyl substitution on these compounds, since the activities obtained through their corresponding arylacetic acid derivatives (i.e., α-demethylated derivatives) or α,α-dimethyl-substituted compounds are less than what is observed for the parent profens. Unfortunately, this implies a generalization in structure-activity relationships of profens in such a way that a mono-(non-methyl)alkyl group or dialkyl substituent replaced at the α-position of a profen analogue results in abolished activity. Therefore, within this study, we aimed to question this generalization employing ibuprofen, flurbiprofen, and naproxen as model compounds. A series of α-(non-methyl)alkyl-substituted ibuprofen and flurbiprofen analogues as well as α,α-dialkyl-substituted ibuprofen, flurbiprofen, and naproxen derivatives were synthesized and screened for their potential to inhibit cyclooxygenase enzymes. In addition, since profens have negligible potential to inhibit lipoxygenase enzymes, the effect of such derivatization was also questioned in lipoxygenase inhibition assays. The findings only partially agreed with the current structure-activity approach of profens and the activity results of some compounds were found as beyond ordinary.
authors.affiliation: Nobel R&D Center (Nobel İlaç Ar-Ge Merkezi), Duzce, Turkey; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Eastern Mediterranean University, Famagusta, Cyprus.
authors.forename: Hayrettin O
authors.initials: HO
authors.lastname: Gülcan
authors.forename: Serdar
authors.initials: S
authors.lastname: Ünlü
authors.forename: Anatoli
authors.initials: A
authors.lastname: Dimoglo
authors.forename: Yasemin
authors.initials: Y
authors.lastname: Şahin
authors.forename: İlker
authors.initials: İ
authors.lastname: Esiringu
authors.forename: Tuba
authors.initials: T
authors.lastname: Erçetin
authors.forename: Demet
authors.initials: D
authors.lastname: Öz
authors.forename: Mustafa F
authors.initials: MF
authors.lastname: Şahin
mesh_terms: D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D015195:Drug Design; D005480:Flurbiprofen / Q000138:chemical synthesis / Q000494:pharmacology; D007052:Ibuprofen / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D015394:Molecular Structure; D009288:Naproxen / Q000138:chemical synthesis / Q000494:pharmacology; D011422:Propionates / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D016859:Lipoxygenase Inhibitors; D011422:Propionates; D009288:Naproxen; D005480:Flurbiprofen; D001094:Arachidonate 5-Lipoxygenase; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D007052:Ibuprofen
keywords: COX; LOX; Profens; α,α-Disubstitution; α-Monosubstitution