Basic Pharmacological Characterization of EV-34, a New H 2 S-Releasing Ibuprofen Derivative

• Published in: Molecules (Basel, Switzerland) Vol. 26; no. 3
• Main Authors: Gyöngyösi, Alexandra, Verner, Vivien, Bereczki, Ilona, Kiss-Szikszai, Attila, Zilinyi, Rita, Tósaki, Árpád, Bak, István, Borbás, Anikó, Herczegh, Pál, Lekli, István
• Format: Journal Article
• Language: English
• Published: Switzerland 24.01.2021
• Subjects: Animals; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Cell Line; Cyclooxygenase Inhibitors - chemistry; Cyclooxygenase Inhibitors - pharmacology; Hydrogen Sulfide - chemistry; Ibuprofen - chemistry; Ibuprofen - pharmacology; Inflammation - drug therapy; Male; Oxidative Stress - drug effects; Prostaglandin-Endoperoxide Synthases - metabolism; Rats; Rats, Sprague-Dawley; anti-inflammatory property; gasotransmitter; hydrogen-sulfide; H2S-releasing-ibuprofen; thiolacetic acid
• ISSN: 1420-3049

Cardioprotective effects of H S are being suggested by numerous studies. Furthermore, H S plays a role in relaxation of vascular smooth muscle, protects against oxidative stress, and modulates inflammation. Long-term high-dose use of NSAIDs, such as ibuprofen, have been associated with enhanced cardiovascular risk. The goal of the present work is the synthesis and basic pharmacological characterization of a newly designed H S-releasing ibuprofen derivative. Following the synthesis of EV-34, a new H S-releasing derivative of ibuprofen, oxidative stability assays were performed (Fenton and porphyrin assays). Furthermore, stability of the molecule was studied in rat serum and liver lysates. H S-releasing ability of the EC-34 was studied with a hydrogen sulfide sensor. MTT (3-(4,5-dimethylthiazol 2-yl)-2,5-(diphenyltetrazolium bromide)) assay was carried out to monitor the possible cytotoxic effect of the compound. Cyclooxygenase (COX) inhibitory property of EV-34 was also evaluated. Carrageenan assay was carried out to compare the anti-inflammatory effect of EV-34 to ibuprofen in rat paws. The results revealed that the molecule is stable under oxidative condition of Fenton reaction. However, EV-34 undergoes biodegradation in rat serum and liver lysates. In cell culture medium H S is being released from EV-34. No cytotoxic effect was observed at concentrations of 10, 100, 500 µM. The COX-1 and COX-2 inhibitory effects of the molecule are comparable to those of ibuprofen. Furthermore, based on the carrageenan assay, EV-34 exhibits the same anti-inflammatory effect to that of equimolar amount of ibuprofen (100 mg/bwkg). The results indicate that EV-34 is a safe H S releasing ibuprofen derivative bearing anti-inflammatory properties.