Design, synthesis and biological assessment of new selective COX-2 inhibitors including methyl sulfonyl moiety

• Published in: European journal of medicinal chemistry Vol. 209; p. 112918
• Main Authors: Sağlık, Begüm Nurpelin, Osmaniye, Derya, Levent, Serkan, Çevik, Ulviye Acar, Çavuşoğlu, Betül Kaya, Özkay, Yusuf, Kaplancıklı, Zafer Asım
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 01.01.2021; Elsevier
• Subjects: Amino Acid Sequence; Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis; Anti-Inflammatory Agents, Non-Steroidal - metabolism; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Catalytic Domain; Celecoxib - pharmacology; Chemistry, Medicinal; Cyclooxygenase 1 - metabolism; Cyclooxygenase 2 - metabolism; Cyclooxygenase 2 Inhibitors - chemical synthesis; Cyclooxygenase 2 Inhibitors - metabolism; Cyclooxygenase 2 Inhibitors - pharmacology; Dimethyl Sulfoxide - chemistry; Enzyme inhibition; Humans; Hydrazines - chemistry; Life Sciences & Biomedicine; Methyl sulfonyl; Molecular docking; Molecular Docking Simulation; Pharmacology & Pharmacy; Protein Binding; Science & Technology; Selective COX-2 inhibitor; Structure-Activity Relationship; Sulfonamides - pharmacology; Sulfones - chemistry; Thiazole; Thiazoles - chemical synthesis; Thiazoles - metabolism; Thiazoles - pharmacology; Enzyme inhibition; Selective COX-2 inhibitor; Thiazole; Molecular docking; Methyl sulfonyl; DERIVATIVES; ORAL DRUGLIKENESS; DISCOVERY; PREDICTION; SOLUBILITY
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2020.112918

Nonsteroidal anti-inflammatory drugs (NSAIDs) cause peptic lesions in the gastrointestinal mucosa by inhibiting the cyclooxygenase-1 (COX-1) enzyme. Selective COX-2 inhibition causes decreased side effects over current NSAIDs. Therefore, the studies about selective inhibition of COX-2 enzyme are very important for new drug development. The design, synthesis and biological activity evaluation of novel derivatives bearing thiazolylhydrazine-methyl sulfonyl moiety as selective COX-2 inhibitors were aimed in this paper. The structures of synthesized compounds were assigned using different spectroscopic techniques such as 1H NMR, 13C NMR and HRMS. In addition, the estimation of ADME parameters for all compounds was carried out using in silico process. The evaluation of in vitro COX-1/COX-2 enzyme inhibition was applied according to the fluorometric method. According to the enzyme inhibition results, synthesized compounds showed the selectivity against COX-2 enzyme inhibition as expected. Compounds 3a, 3e, 3f, 3g, 3i and 3j demonstrated significant COX-2 inhibition potencies. Among them, compound 3a was found to be the most effective derivative with an IC50 value of 0.140 ± 0.006 μM. Moreover, it was seen that compound 3a displayed a more potent inhibition profile at least 12-fold than nimesulide (IC50 = 1.684 ± 0.079 μM), while it showed inhibitory activity at a similar rate of celecoxib (IC50 = 0.132 ± 0.005 μM). Molecular modelling studies aided in the understanding of the interaction modes between this compound and COX-2 enzyme. It was found that compound 3a had a significant binding property. In addition, the selectivity of obtained derivatives on COX-2 enzyme could be explained and discussed by molecular docking studies. [Display omitted] •10 New thiazole derivatives including methyl sulfonyl scaffolds were synthesized.•All synthesized compounds showed selective COX-2 enzyme inhibition potency.•The compound 3a indicated important inhibitory activity against COX-2 enzyme.•A good ADME profile was predicted for all compounds.•Interaction modes between the COX-2 and compound 3a were determined by docking studies.