Synthesis, characterization, molecular modelling and biological evaluation of thieno‐pyrimidinone methanesulphonamide thio‐derivatives as non‐steroidal anti‐inflammatory agents

Clinical and Experimental Pharmacology and Physiology - Tập 45 Số 9 - Trang 952-960 - 2018
Adriana Carol Eleonora Graziano1, Giovanna Pannuzzo1, Ettore Salemi2, Andrea Santagati2, Rosanna Avola1, Emanuele Longo2, Venera Cardile1
1Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, Catania, Italy
2Department of Drug Sciences, University of Catania, Catania, Italy

Tóm tắt

SummaryThis study reports the synthesis, molecular docking and biological evaluation of eight (5‐8 and 5a‐8a) newly synthesized thieno‐pyrimidinone methanesulphonamide thio‐derivatives. The synthetic route used to prepare the new isomers thioaryl and thio‐cycloesyl derivatives of the heterocyclic system 6‐phenylthieno[3,2]pyrimidinone was economically and environmentally very advantageous and characterized by the simplicity of procedure, reduction in isolation steps, purification phases, time, costs and waste production. The study in silico for the evaluation of cyclooxygenase (COX)‐1 and COX‐2 selective inhibition was carried out by AutoDock Vina, an open‐source program for doing molecular docking which predicts the preferred orientation of one molecule to a second when bound to each other to form a stable complex. The research in vitro for the biological evaluation was performed by using human cartilage and chondrocytes cultures treated with 10 ng/mL of interleukin‐1beta as inflammation models. The anti‐inflammatory activity of each new compound at the concentration of 10 μmol/L was determined by assaying COX‐2, inducible nitric oxide synthetase (iNOS) and intercellular adhesion molecule 1 (ICAM 1) through Western blot. The examined derivatives showed interesting pharmacological activity, and the compound N‐[2‐[2,4‐difluorophenyl)thio]‐4‐oxo‐6‐phenylthieno[3,2‐d]pyridine‐34H‐yl]methanesulphonamide (7) was excellent COX‐2 inhibitor. In agreement with the biological data, compound 7 was able to fit into the active site of COX‐2 with highest interaction energy. These results can support the design of novel specific inhibitors of COX‐2 by the comparative modelling of COX‐1 and COX‐2 enzymes with the available pharmacophore.

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Thông tin xuất bản

Clinical and Experimental Pharmacology and Physiology

Tập 45 Số 9

952-960

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