Design, synthesis and anti-inflammatory assessment of certain substituted 1,2,4-triazoles bearing tetrahydroisoquinoline scaffold as COX 1/2-inhibitors.

Autor: Abo-Elmagd MI; Medicinal and Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre (ID: 60014618), P.O. 12622, Dokki, Giza, Egypt., Hassan RM; Medicinal and Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre (ID: 60014618), P.O. 12622, Dokki, Giza, Egypt., Aboutabl ME; Medicinal and Pharmaceutical Chemistry Department, Pharmacology Group, Pharmaceutical and Drug Industries Research Institute, National Research Centre (ID: 60014618), P.O. 12622, Dokki, Giza, Egypt., Amin KM; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt., El-Azzouny AA; Medicinal and Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre (ID: 60014618), P.O. 12622, Dokki, Giza, Egypt., Aboul-Enein MN; Medicinal and Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre (ID: 60014618), P.O. 12622, Dokki, Giza, Egypt. Electronic address: mnaboulenein@yahoo.com.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2024 Sep; Vol. 150, pp. 107577. Date of Electronic Publication: 2024 Jun 18.
DOI: 10.1016/j.bioorg.2024.107577
Abstrakt: Aiming to discover effective and safe non-steroidal anti-inflammatory agents, a new set of 1,2,4-triazole tetrahydroisoquinoline hybrids 9a-g, 11a-g and 12a-g was synthesized and evaluated as inhibitors of COX-1 and COX-2. In order to overcome the adverse effects of highly selective COX-2 and non-selective COX-2 inhibitors, the compounds of this study were designed with the goal of obtaining moderately selective COX-2 inhibitors. In this study compounds 9e, 9g and 11f are the most effective derivatives against COX-2 with IC 50 values 0.87, 1.27 and 0.58 µM, respectively which are better than or comparable to the standard drug celecoxib (IC 50  = 0.82 µM) but with lower selectivity indices as required by our goal design. The results of the in vivo anti-inflammatory inhibition test revealed that compounds 9e, 9g and 11f displayed a higher significant anti-inflammatory activity than celecoxib at all-time intervals. In addition, these compounds significantly decreased the production of inflammatory mediators PGE-2, TNF-ɑ and IL-6. Compounds 9e, 9g and 11f had a safe gastric profile compared to indomethacin, also compound 11f (ulcerogenic index = 1.33) was less ulcerous than the safe celecoxib (ulcerogenic index = 3). Moreover, histopathological investigations revealed a normal architecture of both paw skin and gastric mucosa after oral treatment of rats with compound 11f. Furthermore, molecular docking studies were performed on COX-1 and COX-2 to study the binding pattern of compounds 9e, 9g and 11f on both isoenzymes.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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