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

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          Abstract

          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.

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          Author and article information

          Journal
          Eur J Med Chem
          European journal of medicinal chemistry
          Elsevier BV
          1768-3254
          0223-5234
          Jan 01 2021
          : 209
          Affiliations
          [1 ] Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, 26470, Eskişehir, Turkey; Doping and Narcotic Compounds Analysis Laboratory, Faculty of Pharmacy, Anadolu University, 26470, Eskişehir, Turkey.
          [2 ] Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Zonguldak Bülent Ecevit University, 67600, Zonguldak, Turkey.
          [3 ] Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, 26470, Eskişehir, Turkey. Electronic address: zakaplan@anadolu.edu.tr.
          Article
          S0223-5234(20)30890-4
          10.1016/j.ejmech.2020.112918
          33071054

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