An operationally simple, one‐pot, convenient synthesis, and in vitro anti‐inflammatory activity of some new spirotriazolotriazine derivatives

• Published in: Journal of heterocyclic chemistry Vol. 61; no. 1; pp. 146 - 162
• Main Authors: El‐Saghier, Ahmed M., Enaili, Souhaila S., Abdou, Aly, Hamed, Amany M., Kadry, Asmaa M.
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Inc 01-01-2024; Wiley Subscription Services, Inc
• Subjects: Benzene; Chemical analysis; Hemolysis; Ketones; Molecular docking; NMR; Nuclear magnetic resonance; Spectrum analysis; Sulfonamides; Synthesis
• ISSN: 0022-152X; 1943-5193
• DOI: 10.1002/jhet.4752

The wide biological actions of triazolotriazine hybrids, benzene‐sulfonamide derivatives, exhibit a good chance of displaying in vitro anti‐inflammatory effects. An operationally simple one‐pot, three‐component, and convenient synthesis method is used toward the synthesis of a series of diverse 2‐(2‐(4‐amino)‐1,3,5‐triazaspiro‐1,4‐dien‐2‐yl) hydrazinyl)‐N‐(4‐sulfamoylphenyl)‐2‐thioxoacetamides, which generated via reaction of 2‐hydrazinyl‐N‐(4‐sulfamoylphenyl)‐2‐thioxoacetamide, cyanoguanidine, and cyclic/acyclic ketones and were characterized by spectral analysis (IR, Nuclear Magnetic Resonance: 1H‐NMR, 13C‐NMR, and elemental analysis). The spirotriazolotriazine derivatives are obtained with up to 95% yield, and their structure–activity relationship was discussed. All compounds were tested for in vitro anti‐inflammatory potential using the inhibition of RBC hemolysis technique and COX inhibition assay. The results from RBC hemolysis technique demonstrated that almost all evaluated compounds exhibited significant in vitro anti‐inflammatory efficacy. More specifically, compounds 7, 8, and 12 have superior membrane stability over indomethacin as a standard drug. At concentrations of 400, 600, 800, and 1000 μg/mL, compound 12 demonstrated highly significant inhibition of RBC hemolysis with 95.2%, 97.3%, 98.9%, and 99.8%, respectively, compared with indomethacin at the same concentrations (94.5%, 97.3%, 98.5%, and 99.3%, respectively). COX assay indicated that compounds 7, 8, and 12 exhibited excellent COX‐2 inhibition percentage (98.51 ± 0.01, 98 ± 0.01, and 98.97 ± 0.06, respectively) at 150 μg/mL using indomethacin (97.3 ± 0.005). Furthermore, an investigation using molecular docking against COX‐2 (pdb ID: 5IKT) was used to analyze the anti‐inflammatory properties of all studied substances. When compared to indomethacin, molecular docking research showed a strong connection with the intended protein and an elevated docking score. According to in vitro anti‐inflammatory action and computational approach, they show promise as a therapeutic candidate for the treatment of inflammatory diseases.
A convenient green synthetic approach to the synthesis of a novel class of Spirotriazolotriazine derivatives with high Anti‐inflammatory Activity.