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

Abstract

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-1ylsulfonyl)phenyl]-1-[4-(4-cyanophenoxy)benzylidene]thiosemicarbazide (2c) was the most potent and selective COX-1 inhibitor in this series, with an IC 50 value of 1.89 ± 0.04 µM. On the other hand, 4-[4-(piperidin-1-ylsulfonyl)phenyl]-1-[4-(4nitrophenoxy)benzylidene]thiosemicarbazide (2b) was identified as a nonselective COX inhibitor (COX-1 IC 50 = 13.44 ± 0.65 µM, COX-2 IC 50 = 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 2cdiminished 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 druglikeness and oral bioavailability. It can be concluded that these compounds may act as orally bioavailable anti-inflammatory and antioxidant agents.

Synthesis and Caracterizations of New Thiosemicarbazone and Thiazole Derivatives From Polycyclic Chiral 1,5‐Diketones

“…In the 13 C-NMR spectrum of 3 a, the peak at 199. The 2D-NMR spectra of 3 a are given in the supporting information and appear to confirm the proposed structure.…”

“…In this study, 14 new thiosemicarbazone derivatives (3 a-n) were obtained from the reaction of chiral polycyclic 1,5diketone derivatives (1 a-n) with thiosemicarbazide (2), and 14 new thiazole derivatives (5 a-n) were obtained from the reaction of thiosemicarbazones (3 a-n) with 2-bromoacetophenone (4). The chemical structures of the synthesized compounds were determined by spectroscopic methods ( 1 H-NMR, 13 C-NMR, 2D-NMR, FT-IR and Q-TOF LC/MS). The spectral analyzes performed support the proposed configurations of the compounds.…”

“…IR spectra (ATR) were recorded on a Bruker Tensor II FT-IR spectrometer. 1 H-NMR and 13 C-NMR spectra were recorded on a JEOL (400 MHz) JNM-ECZ400S/L1 NMR instrument and 2D-NMR spectra were recorded on a Bruker Avance DPX-400 instrument in CDCl 3 at room temperature; δ in ppm relative to tetramethylsilane (TMS), with J in hertz (Hz). Agilent Technology Inc. of 1260 Infinity HPLC System was coupled with 6530 Q-TOF LC/MS detector and ZORBAX SB-C18 (2.1×50 mm, 1.8 μm) column.…”

“…Agilent Technology Inc. of 1260 Infinity HPLC System was coupled with 6530 Q-TOF LC/MS detector and ZORBAX SB-C18 (2.1×50 mm, 1.8 μm) column. 1 H-NMR, 13 C-NMR, and Q-TOF LC/MS analyses of the compounds were carried out at the Advanced Technology Application and Research Center (CUTAM) of Sivas Cumhuriyet University and 2D-NMR analyses were carried out at the Advanced Technology Application and Research Center (GUBİTAM) of Tokat Gaziosmanpaşa University.…”

“…[4] When look at the literature, it is seen that there are many studies on thiosemicarbazones and the scope of these studies is generally on the synthesis, biochemistry, structural properties, biological activities and analytical applications of thiosemicarbazones. [5][6][7][8] In the literature, it is seen that various thiosemicarbazone derivatives with antimicrobial, [9] antituberculosis, [10] anti-HIV, [11] anticonvulsant, [12] analgesic, [13] antitumor, [14] and antifungal [15] activities have been reported. In addition, there are many studies on ionophore properties of thiosemicarbazones.…”