Rational Design and Synthesis of New Selective COX-2 Inhibitors with In Vivo PGE2-Lowering Activity by Tethering Benzenesulfonamide and 1,2,3-Triazole Pharmacophores to Some NSAIDs

El-Dershaby, Nada H; El-Hawash, Soad A.M.; Kassab, Shaymaa E.; Daabees, Hoda G.; Moneim, Ahmed E. Abdel; El-Miligy, Mostafa M.M.

doi:10.3390/ph15101165

Cited by 5 publications

(1 citation statement)

References 38 publications

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“…Due to the potential for biological action of each system and the reciprocal interaction between the two heterocyclic rings [22–24], the hybridization of 1,2,4‐triazole and 1,3,5‐triazine in a single molecule could end up as fresh compounds with higher pharmacological activity as anti‐inflammatory agonists [25–28].…”

Section: Introductionmentioning

confidence: 99%

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

El‐Saghier,

Enaili,

Abdou

et al. 2023

Journal of Heterocyclic Chem

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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.

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Section: Introductionmentioning

confidence: 99%

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

El‐Saghier,

Enaili,

Abdou

et al. 2023

Journal of Heterocyclic Chem

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Recent advances in triazole-benzenesulfonamide hybrids and their biological activities

et al. 2023

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Re-design and evaluation of diclofenac-based carborane-substituted prodrugs and their anti-cancer potential

Selg,

Gordić,

Krajnović

et al. 2024

Sci Rep

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In this study, we investigated a novel anti-cancer drug design approach by revisiting diclofenac-based carborane-substituted prodrugs. The redesigned compounds combine the robust carborane scaffold with the oxindole framework, resulting in four carborane-derivatized oxindoles and a unique zwitterionic amidine featuring a nido-cluster. We tested the anti-cancer potential of these prodrugs against murine colon adenocarcinoma (MC38), human colorectal carcinoma (HCT116), and human colorectal adenocarcinoma (HT29). The tests showed that diclofenac and the carborane-substituted oxindoles exhibited no cytotoxicity, the dichlorophenyl-substituted oxindole had moderate anti-cancer activity, while with the amidine this effect was strongly potentiated with activity mapping within low micromolar range. Compound 3 abolished the viability of selected colon cancer cell line MC38 preferentially through strong inhibition of cell division and moderate apoptosis accompanied by ROS/RNS depletion. Our findings suggest that carborane-based prodrugs could be a promising direction for new anti-cancer therapies. Inhibition assays for COX-1 and COX-2 revealed that while diclofenac had strong COX inhibition, the re-engineered carborane compounds demonstrated a varied range of anti-cancer effects, probably owing to both, COX inhibition and COX-independent pathways.

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Rational Design and Synthesis of New Selective COX-2 Inhibitors with In Vivo PGE2-Lowering Activity by Tethering Benzenesulfonamide and 1,2,3-Triazole Pharmacophores to Some NSAIDs

Cited by 5 publications

References 38 publications

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

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

Recent advances in triazole-benzenesulfonamide hybrids and their biological activities

Re-design and evaluation of diclofenac-based carborane-substituted prodrugs and their anti-cancer potential

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