In Vitro Cytotoxicity of Methano[1,2,4]Triazolo-[1,5-C][1,3,5]Benzoxadiazocine Derivatives and Their Effects on Nitrite and Prostaglandin E2 (PGE2) Levels

DOĞAN İ. S., Gümüş M. K., Gorobets N. Y., Reis R., Orak D., Sipahi H., ...More

Pharmaceutical Chemistry Journal, vol.56, no.6, pp.769-776, 2022 (SCI-Expanded) identifier identifier

  • Publication Type: Article / Article
  • Volume: 56 Issue: 6
  • Publication Date: 2022
  • Doi Number: 10.1007/s11094-022-02708-w
  • Journal Name: Pharmaceutical Chemistry Journal
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, Biotechnology Research Abstracts, Chemical Abstracts Core, EMBASE
  • Page Numbers: pp.769-776
  • Keywords: anti-inflammatory activity, analgesic, Biginelli reaction, in vitro cytotoxicity, molecular docking, nitrite level, PGE(2), HIRSHFELD SURFACE-ANALYSIS, MODIFIED BIGINELLI REACTION, CRYSTAL-STRUCTURE, E SYNTHASE, INHIBITION, PROTEIN, 3-AMINO-1,2,4-TRIAZOLE, MECHANISM, DISCOVERY, DOCKING
  • Karadeniz Technical University Affiliated: Yes


© 2022, Springer Science+Business Media, LLC, part of Springer Nature.Biological activity of the Biginelli type heterocycles is extremely broad and provides a suitable platform for the discovery of potent small drug-like molecules. Such activity of 3,4-dihydropyrimidin-2(1H)-one (DHPM) derivatives is widely known, whereas their oxygen-bridged analogs, benzoxadiazocines, are presented quite rarely in the literature. In this study, a series of new methano[1,2,4]triazolo[1,5-c][1,3,5]benzoxadiazocine derivatives (3a-3j) were evaluated in vitro for their activities and molecular docking features. According to the molecular docking study, COX-2 and PGE2S appeared as likely targets responsible for the reduced PGE2 levels caused by the title compounds. The cytotoxicity of compounds 3a-3g, 3j was evaluated on RAW 264.7 murine macrophage cell line by MTT assay after treatment for 24 h with various doses (25, 50, 100 μM) of these compounds. Then, compounds admitting cell viability higher than 70% were tested for their anti-inflammatory activity at non-toxic doses by evaluating the nitrite level of cell supernatants with the Griess reagent. Compounds 3c and 3f demonstrated significant inhibition of nitrite production (by 29 and 25%, respectively) at 100 μM (p < 0.05). These compounds significantly inhibited PGE2 production, thus suggesting analgesic activity.