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The synthesis, the antitumor activity, the SAR and, whenever described, the possible mode of action of 1,2,4-triazine derivatives, their N -oxides, N , N′ -dioxides as well as the benzo- and hetero-fused systems are reported. Herein are treated derivatives disclosed to literature from the beginning of this century up to 2016. Among the three possible triazine isomers, 1,2,4-triazines are the most studied ones and many derivatives having remarkable antitumor activity have been reported in the literature and also patented reaching advanced phases of clinical trials. [ABSTRACT FROM AUTHOR]

A novel series of triazine-triazole derivatives 7a – 7m were synthesized, characterized by 1 H NMR and evaluated for their α-glucosidase inhibitory activity. All the synthesized compounds displayed potent α-glucosidase inhibitory activity with IC 50 range of 11.63 ± 0.15 to 37.44 ± 0.35 μM, when compared to the standard drug acarbose (IC 50 = 817.38 ± 6.27 μM). Among the series, compound 7i (IC 50 = 11.63 ± 0.15 μM) bearing 2,5-dichloro substitution at phenyl ring, represented the most potent α-glucosidase inhibitory activity. Molecular docking studies of the most active compounds with the homology modelled α-glucosidase were also performed to explore the possible inhibitory mechanism. Our studies shown that these triazine-triazole derivatives are a new class of α-glucosidase inhibitors. [ABSTRACT FROM AUTHOR]

Yellow fever disease is one of public health concerns in the tropics. Despite its significant medicinal and economic impact among large groups of the population, there is a lack of effective treatment against yellow fever. In this regard, here we describe the synthesis of a series of new 6-aryl-3-R-amino-1,2,4-triazin-5(4 H)-ones and evaluation of their in vitro inhibitory activity against yellow fever virus. Among all tested compounds 4 derivatives possessing strong inhibitory activity at μM concentrations were identified. All the active compounds revealed a good toxicity profile. These facts make the compounds interesting candidates for further evaluation of their efficacy in the treatment of yellow fever virus infection in vivo. [Display omitted] • A series of novel 1,2,4-triazines was evaluated for Yellow fever virus inhibition. • Several compounds displayed inhibition activities at micromolar level. • Remarkable selective inhibitory properties were identified. • SAR analysis was carried out. • The studied compounds provide a promising scaffold for further optimization. [ABSTRACT FROM AUTHOR]

A series of triazin–3(2 H )–one derivatives bearing 1,3,4–oxadiazole (4a–4o) were synthesized, characterized and evaluated for anti–inflammatory and analgesic activities. Preliminary in vitro anti–inflammatory activity was assessed using an albumin denaturation assay. The promising compounds were further evaluated in acute, sub–chronic and chronic animal models of inflammation. Derivatives 4d, 4e, 4g, 4j and 4l exhibited significant anti–inflammatory activity with reduced ulcerogenic, hepatotoxic and renotoxic liabilities compared to standard indomethacin. These potential derivatives were also evaluated for in vivo analgesic activity using a writhing model and the formalin-induced paw licking response in mice. Compounds 4d , 4e and 4g exhibited comparable analgesic activity, whereas 4j and 4l yielded moderate effects. The specificity of compounds 4d, 4e , 4g , 4j , and 4l to inhibit (cyclooxygenase–1) COX–1 and (cyclooxygenase–2) COX–2 isozymes and their kinetics were also determined via an in vitro COX inhibition assay. In silico docking studies were performed using a molecular dynamics simulation of the most active compound 4d (COX–2 IC 50 : 3.07 μM) at the COX–2 active site. The outcome of this exercise helped to verify the consensual interaction of these compounds with the enzyme. [ABSTRACT FROM AUTHOR]

Abstract: The reaction of 5,6-diphenyl-3-hydrazino-1,2,4-triazine (1) with bis(methylthio)methylene]malononitrile (2) afforded 5-amino-1-(5,6-diphenyl-1,2,4-triazin-3-yl)-3-(methylthio)-1H-pyrazole-4-carbonitrile (3). Compound 3 reacted with thiourea to give 3,4-diaminopyrazolo[3,4-d]pyrimidine 5, which was treated with benzoyl chloride to give pyrazolo[5,4,3-kl]pyrimido[4,3-d]pyrimidine 6. Treatment of 3 with acetic anhydride produced 3-methylthio-pyrazolo[3,4-d]pyrimidine derivative 7, which was allowed to react with hydrazine hydrate to give the corresponding hydrazino derivative 8. Heterocyclization of 8 with benzoyl chloride and sodium pyruvate afforded the polyfused heterocycles 9 and 10, respectively. Reaction of 3 with benzoylacetone yielded pyrazolo[3,4-b]pyridine 12, which was allowed to react with malononitrile and acetanilide to get heterocyclic systems 13 and 14, respectively. Interaction of 3 with cyanoacetone gave pyrazolo[3,4-b]pyridine 15, which was refluxed in formic acid to yield pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidine 16. Reaction of 3 with 2 afforded the triazinylpyrazole derivative 17, which was reacted with hydrazine hydrate to give dipyrazolo[1,5-a:3′,4′-d]pyrimidine 19. Furthermore, treatment of the latter compound with methyl anthranilate furnished tetraheterocyclic compound 21. Structures of the products have been determined by elemental analysis and spectral studies. All compounds have been screened for their antibacterial and antifungal activities. Compounds 9, 10, 13, 19 and 21 showed maximum activity comparable to the standard drugs with lower toxicity in the case of 9 and 10. [Copyright &y& Elsevier]

The synthesis of a group of 1,3,4-oxadiazoles, 1,2,4-triazoles, 1,3,4-thiadiazoles and 1,2,4-triazine derived from 2-[(2,6-dichloroanilino) phenyl] acetic acid is described. The structures of new compounds are supported by IR, 1H-NMR and Mass spectral data. These compounds were tested in vivo for their anti-inflammatory activity. The compounds, which showed activity comparable to the standard drug diclofenac, were screened for their analgesic, ulcerogenic and lipid peroxidation activities. Ten new compounds, out of 28 showed very good anti-inflammatory activity in the carrageenin induced rat paw edema test, with significant analgesic activity in the acetic acid induced writhing test together with negligible ulcerogenic action. The compounds, which showed less ulcerogenic action, also showed reduced malondialdehyde content (MDA), which is one of the byproduct of lipid peroxidation. The study showed that the compounds inhibited the induction of gastric mucosal lesions and it can be suggested from our results that their protective effects may be related to inhibition of lipid peroxidation in the gastric mucosa. [Copyright &y& Elsevier]

Based on the observed pharmacophoric structural features for the reported dual COX/15-LOX inhibitors and inspired by the abundance of COX/LOX inhibitory activities reported for the 1,2,4-triazine and quinoline scaffolds, we designed and synthesized novel 1,2,4-triazine-quinoline hybrids (8a-n). The synthesized hybrids were evaluated in vitro as dual COXs/15-LOX inhibitors. The new triazine-quinoline hybrids (8a-n) exhibited potent COX-2 inhibitory profiles (IC 50 = 0.047–0.32 μM, SI ∼ 20.6–265.9) compared to celecoxib (IC 50 = 0.045 μM, SI ∼ 326). Moreover, they revealed potent inhibitory activities against 15-LOX enzyme compared to reference quercetin (IC 50 = 1.81–3.60 vs. 3.34 μM). Hybrid 8e was the most potent and selective dual COX-2/15-LOX inhibitor (COX-2 IC 50 = 0.047 μM, SI = 265.9, 15-LOX IC 50 = 1.81 μM). These hybrids were further challenged by their ability to inhibit NO, ROS, TNF-α, IL-6 inflammatory mediators, and 15-LOX product, 15-HETE, production in LPS-activated RAW 264.7 macrophages cells. Compound 8e was the most potent hybrid in reducing ROS and 15-HETE levels showing IC 50 values of 1.02 μM (11-fold more potent than that of celecoxib, IC 50 = 11.75 μM) and 0.17 μM (about 43 times more potent than celecoxib, IC 50 = 7.46 μM), respectively. Hybrid 8h exhibited an outstanding TNF-α inhibition with IC 50 value of 0.40 μM which was about 25 times more potent than that of celecoxib and diclofenac (IC 50 = 10.69 and 10.27 μM, respectively). Docking study of the synthesized hybrids into the active sites of COX-2 and 15-LOX enzymes ensures their favored binding affinity. To our knowledge, herein we reported the first 1,2,4-triazine-quinoline hybrids as dual COX/15-LOX inhibitors. [Display omitted] • Novel 1,2,4-triazine-quinoline hybrids (8a-n) were designed and synthesized. • The synthesized hybrids were evaluated in vitro as dual COXs/15-LOX inhibitors. • Hybrid 8e was the most potent and selective dual COX-2/15-LOX inhibitor. • Compound 8e was the most potent hybrids in reducing ROS and 15-HETE levels. • Hybrid 8h exhibited an outstanding TNF-α inhibition about 25 times more potent than that of celecoxib. [ABSTRACT FROM AUTHOR]