Design, Synthesis and Biological Evaluation of New N-Acyl Hydrazones with a Methyl Sulfonyl Moiety as Selective COX-2 Inhibitors


OSMANİYE D., SAĞLIK B. N., LEVENT S., ÖZKAY Y., KAPLANCIKLI Z. A.

CHEMISTRY & BIODIVERSITY, cilt.18, sa.11, 2021 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 18 Sayı: 11
  • Basım Tarihi: 2021
  • Doi Numarası: 10.1002/cbdv.202100521
  • Dergi Adı: CHEMISTRY & BIODIVERSITY
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Aquatic Science & Fisheries Abstracts (ASFA), CAB Abstracts, Chemical Abstracts Core, EMBASE, MEDLINE, Veterinary Science Database
  • Anahtar Kelimeler: N-acylhydrazone, methylsulfonyl, COX-2 inhibition, docking studies, DERIVATIVES, CYCLOOXYGENASE-2, DRUGS
  • Anadolu Üniversitesi Adresli: Evet

Özet

The mechanism of action of nonsteroidal anti-inflammatory drugs (NSAIDs) is inhibition of specific prostaglandin (PG) synthesis by inhibition of cyclooxygenase (COX) enzymes. The two COX isoenzymes show 60 % similarity. It is known that the nonspecific side effects of conventional NSAIDs are physiologically caused by inhibition of the COX-1 enzyme. Therefore, the use of COX-2 selective inhibitors is seen to be a more beneficial approach in reducing these negative effects. However, some of the existing COX-2 selective inhibitors show cardiovascular side effects. Therefore, studies on the development of new selective COX-2 inhibitors remain necessary. It is important to develop new COX-2 inhibitors in the field of medicinal chemistry. Accordingly, novel N-acyl hydrazone derivatives were synthesized as new COX-2 inhibitors in this study. The hydrazone structure, also known for its COX activity, is important in terms of many biological activities and was preferred as the main structure in the design of these compounds. A methyl sulfonyl pharmacophore was added to the structure in order to increase the affinity for the polar side pocket present in the COX-2 enzyme. It is known that methyl sulfonyl groups are suitable for polar side pockets. The synthesis of the compounds (3a-3j) was characterized by spectroscopic methods. Evaluation of in vitro COX-1/COX-2 enzyme inhibition was performed by fluorometric method. According to the enzyme inhibition results, the obtained compounds displayed the predicted selectivity for COX-2 enzyme inhibition. Compound 3j showed important COX-2 inhibition with a value of IC50=0.143 uM. Interaction modes between the COX-2 enzyme and compound 3j were investigated by docking studies.