A new series of thiosemicarbazone-based anti-inflammatory agents exerting their action through cyclooxygenase inhibition

Altıntop M. D., Sever B., Akalın Çiftçi G., Ertorun İ., ALATAŞ İ. Ö., Özdemir A.

Archiv der Pharmazie, vol.355, no.9, 2022 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 355 Issue: 9
  • Publication Date: 2022
  • Doi Number: 10.1002/ardp.202200136
  • Journal Name: Archiv der Pharmazie
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, CAB Abstracts, Chemical Abstracts Core, Chimica, EMBASE, International Pharmaceutical Abstracts, MEDLINE, Veterinary Science Database
  • Keywords: anti-inflammatory activity, antioxidant activity, cyclooxygenase, molecular docking, thiosemicarbazone, NITRIC-OXIDE, MALONDIALDEHYDE LEVELS, COX-2 INHIBITORS, SEPSIS, ASSAY, DERIVATIVES, DOCKING, DESIGN, SERUM, ACID
  • Eskisehir Osmangazi University Affiliated: Yes


© 2022 Deutsche Pharmazeutische Gesellschaft.In an endeavor to identify potent anti-inflammatory agents, new thiosemicarbazones (TSCs) incorporated into a diaryl ether framework (2a–2l) were prepared and screened for their in vitro inhibitory effects on cyclooxygenases (COXs). 4-[4-(Piperidin-1-ylsulfonyl)phenyl]-1-[4-(4-cyanophenoxy)benzylidene]thiosemicarbazide (2c) was the most potent and selective COX-1 inhibitor in this series, with an IC50 value of 1.89 ± 0.04 µM. On the other hand, 4-[4-(piperidin-1-ylsulfonyl)phenyl]-1-[4-(4-nitrophenoxy)benzylidene]thiosemicarbazide (2b) was identified as a nonselective COX inhibitor (COX-1 IC50 = 13.44 ± 0.65 µM, COX-2 IC50 = 12.60 ± 0.78 µM). Based on molecular docking studies, the diaryl ether and the TSC groups serve as crucial moieties for interactions with pivotal amino acid residues in the active sites of COXs. According to MTT test, compounds 2b and 2c showed low cytotoxic activity toward NIH/3T3 cells. Their in vivo anti-inflammatory and antioxidant potencies were also assessed using the lipopolysaccharide-induced sepsis model. Compounds 2b and 2c diminished high-sensitivity C-reactive protein, myeloperoxidase, nitric oxide, and malondialdehyde levels. Both compounds also caused a significant decrease in aspartate aminotransferase levels as well as alanine aminotransferase levels. In silico pharmacokinetic studies suggest that compounds 2b and 2c possess favorable drug-likeness and oral bioavailability. It can be concluded that these compounds may act as orally bioavailable anti-inflammatory and antioxidant agents.