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Novel 1, 2, 4-Triazole-Thiopyrimidine Hybrids as COX-2 Inhibitors: Synthesis, ADME Profiling, Antioxidant Activity, and Molecular Docking

Thu, 01 Jan 2026 00:00:00 GMT

Название: Novel 1, 2, 4-Triazole-Thiopyrimidine Hybrids as COX-2 Inhibitors: Synthesis, ADME Profiling, Antioxidant Activity, and Molecular Docking Авторы: Karpenko, Yu. V.; Parchenko, V. V.; Panasenko, O. I.; Bihdan, O. A.; Pukhalska, I. O.; Nikiforov, O. A.; Nahorna, N. О.; Nahornyi, V.; Roik, O.; Карпенко, Юрій Вікторович; Парченко, Володимир Володимирович; Панасенко, Олександр Іванович; Бігдан, Олексій Антонович; Пухальська, Ірина Олександрівна; Нікіфоров, Олег Анатолійович; Нагорна, Наталія Олександрівна Аннотация: This work reports the design, synthesis, and multilevel evaluation of 20 new S-alkyl derivatives of 6-(5-mercapto-4-ethyl-4H- 1,2,4-triazol-3-yl)pyrimidine-2,4(1H,3H)-dione as potential selective cyclooxygenase-2 (COX-2) inhibitors with antioxidant properties. The aim was to establish structure–property relationships between the S-alkyl fragment, antioxidant mechanisms, and COX-2 inhibition and to identify lead structures for further optimization. Compounds were obtained by stepwise construction of the 1,2,4-triazole fragment from orotic acid, followed by selective S-alkylation of the mercaptotriazole, and their structures were confirmed by 1H/13C NMR, LC-MS, and elemental analysis. Antiradical activity in vitro was assessed by the DPPH assay with determination of percent inhibition and IC50, whereas COX-1/COX-2 inhibition was evaluated using a fluorescent enzyme assay to obtain IC50 and selectivity index (SI). Density functional theory (DFT) calculations were employed to compare the thermodynamic feasibility of HAT, SET–PT, and SPLET pathways, while molecular docking and molecular dynamics were used to study the affinity and stability of binding to COX-1 and COX-2. A clear increase in antiradical activity was observed in the series 17 < ascorbic acid < 14 < 20 < 13 < 19, reaching 72.34% DPPH inhibition for Compound 19 with IC50(DPPH) = 12.15 ± 3.98 µM , considerably surpassing ascorbic acid. Compound 19 also exhibited the lowest IC50(COX−2) = 24.5 ± 0.9 µM with SI = 8.2 ; Compounds 13 and 20 showed moderate COX-2 selectivity (SI = 1.2 − 1.3 ), whereas 14 and 17 had a COX-1-shifted profile reminiscent of classical NSAIDs. DFT analysis indicated predominance of the SPLET mechanism for most systems, with the lowest ΔG values for 19 and 20, consistent with their high antioxidant activity. The combined experimental and in silico data identify Compound 19 as a primary lead candidate that combines potent antioxidant effects with pronounced, selective COX-2 inhibition and highlight 13 and 20 as promising backup structures for further preclinical studies.

Review of the latest research on the antiviral potential of 1, 2, 4- triazole derivatives

Wed, 01 Jan 2025 00:00:00 GMT

Название: Review of the latest research on the antiviral potential of 1, 2, 4- triazole derivatives Авторы: Borysenko, N. M.; Hubenko, I. Ya.; Parchenko, V. V.; Bushueva, I. V.; Парченко, Володимир Володимирович; Бушуєва, Інна Володимирівна Аннотация: 1,2,4-Triazoles are heterocyclic organic compounds with a broad spectrum of biological activity, including antiviral properties. The advantages of 1,2,4-triazole derivatives as a ―core framework‖ for antiviral compounds include chemical stability, which ensures high resistance to hydrolysis and oxidation, sufficiently high bioavailability, and the potential for chemical modification, among others. Therefore, the search for new 1,2,4-triazole derivatives with antiviral activity remains a relevant task in modern pharmaceutical science. The aim of this study was to analyze and summarize global advancements in recent years regarding the study of antiviral properties of 1,2,4-triazole derivatives and to substantiate the necessity and feasibility of further research in this area. 1,2,4-Triazole is a significant heterocyclic ―framework" actively studied in medicine and pharmacy due to its wide range of biological activities, including antiviral properties. Investigating the influence of functional groups in the triazole structure on its antiviral properties enables the development and implementation of effective drugs. Modifying functional groups in the 1,2,4-triazole molecule allows for the modulation of its activity. Careful structural planning using molecular docking and screening methods facilitates the creation of effective medications against various viruses. Conclusion: Global advancements in the study of antiviral properties of 1,2,4-triazole derivatives in recent years have been analyzed and summarized. The necessity and feasibility of further research in this chosen direction of scientific inquiry have been substantiated.

Development of hybrid molecules based on 1,2,4 triazole for combined anticonvulsant therapy

Wed, 01 Jan 2025 00:00:00 GMT

Название: Development of hybrid molecules based on 1,2,4 triazole for combined anticonvulsant therapy Авторы: Borysenko, N. M.; Parchenko, V. V.; Bushueva, I. V.; Artemenko, L. P.; Chmelova, L. D.; Sukhovyi, G. P.; Парченко, Володимир Володимирович; Бушуєва, Інна Володимирівна Аннотация: The article is devoted to the systematization of modern data on the synthesis of derivatives of 1,2,4-triazole with potential anticonvulsant activity. The unique properties of 1,2,4-triazole as a universal heterocyclic platform that ensures stability, high bioavailability and pharmacological activity are considered. The strategies of molecular modeling of hybrid molecules based on triazole with various pharmacofores that show antiviral, antifungal, antitumor and immunomodulatory properties are analyzed. Particular attention was paid to the Piranian compounds [3,4-C] pyridine nucleus, which found high anticonvulsant, anxiolytic and antidepressant activity. Based on the analysis of literature over the last 10 years, the relationship between structural features, physicochemical characteristics and pharmacological effect has been established. The results create the basis for the development of new anti -epileptic drugs with high efficiency and safety, in particular through purposeful design of molecules.

Derivatives of 1,2,4-triazole as new candidates for the treatment of epileptic disorders

Wed, 01 Jan 2025 00:00:00 GMT

Название: Derivatives of 1,2,4-triazole as new candidates for the treatment of epileptic disorders Авторы: Borysenko, N. M.; Hubenko, I. Ya.; Parchenko, V. V.; Bushuieva, I. V.; Demchenko, A. V.; Sukhovyi, G. P.; Парченко, Володимир Володимирович; Бушуєва, Інна Володимирівна Аннотация: Epilepsy is one of the most common neurological disorders. The use of antiepileptic drugs to control seizures is a crucial aspect of epilepsy treatment and other seizure-associated conditions. However, it presents several challenges related to effectiveness, side effects, and individualized treatment adaptation. In some cases, the disease may become resistant to specific anticonvulsant drugs, meaning that seizures persist despite medication use. This necessitates a shift in treatment approaches and the search for alternative therapies. Derivatives of 1,2,4-triazole are widely utilized in pharmaceutical practice as active substances in effective synthetic drugs. Many of these compounds exhibit relatively low toxicity, making them attractive for clinical application. Some of them can act through multiple mechanisms simultaneously, allowing for the effective treatment of various types of seizures. Conducting research aimed at evaluating the mechanisms of action of triazole derivatives, their impact on neuronal activity, as well as studying their toxicity and pharmacokinetic characteristics, is particularly relevant at this stage. Considering that epilepsy is one of the most widespread neurological diseases worldwide - with approximately 50 million people affected, accounting for 1% of the global population, according to the World Health Organization - the scientific interest in this issue is well justified.