Marginally Designed New Profen Analogues Have the Potential to Inhibit Cyclooxygenase Enzymes

• Published in: Archiv der Pharmazie (Weinheim) 2015-01, Vol.348 (1), p.55-61
• Main Authors: Gülcan, Hayrettin O., Ünlü, Serdar, Dimoglo, Anatoli, Şahin, Yasemin, Esiringu, İlker, Erçetin, Tuba, Öz, Demet, Şahin, Mustafa F.
• Format: Article
• Language: English
• Subjects: Arachidonate 5-Lipoxygenase - metabolism; COX; Cyclooxygenase 1 - metabolism; Cyclooxygenase 2 - metabolism; Cyclooxygenase 2 Inhibitors - chemical synthesis; Cyclooxygenase 2 Inhibitors - pharmacology; Cyclooxygenase Inhibitors - chemical synthesis; Cyclooxygenase Inhibitors - pharmacology; Drug Design; Enzymes; Flurbiprofen - chemical synthesis; Flurbiprofen - pharmacology; Ibuprofen - analogs & derivatives; Ibuprofen - chemical synthesis; Ibuprofen - pharmacology; Lipoxygenase Inhibitors - chemical synthesis; Lipoxygenase Inhibitors - pharmacology; LOX; Molecular Structure; Naproxen - chemical synthesis; Naproxen - pharmacology; Profens; Propionates - chemical synthesis; Propionates - pharmacology; Side effects; Structure-Activity Relationship; α,α‐Disubstitution; α-Disubstitution; α-Monosubstitution
• ISSN: 0365-6233; 1521-4184
• DOI: 10.1002/ardp.201400366

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. The generation of α‐(non‐methyl)‐alkylsubstituted ibuprofen and flurbiprofen analogues as well as α,α‐dialkylsubstituted ibuprofen, flurbiprofen, and naproxen derivatives partially ruled out the generalization in structure activity relationships of profens describing mono‐(non‐methyl)alkyl group or dialkylsubstitutent replaced to the α‐position of a profen analogue results in abolished activity.