Synthesis of 1,3,5-triphenyl-1,2,4-triazole derivatives and their neuroprotection by anti-oxidative stress and anti-inflammation and protecting BBB.

Acute ischemic stroke (AIS) is a serious cardiovascular and cerebrovascular disease; Oxidative stress and neuroinflammation are important factors which destroy blood-brain barrier (BBB) in AIS. In the study, a series of 1,3,5-triphenyl-1,2,4-triazole derivatives were designed and synthesized; the optimal compound 9 was obtained by screening their anti-oxidant and anti-inflammatory effects; the neuroprotection effect of compound 9 was evaluated with a rat middle cerebral artery occlusion (MCAO) model. Subsequently, the mechanism of neuroprotection were explored via Western blot. The results prompt compound 9 maybe exert anti-AIS neuroprotection by inhibiting oxidative stress and neuroinflammation inhibition by inhibiting Keap1, COX-2 and iNOS. At the same time, it can protect BBB by reducing glycocalyx degradation and matrix metallopeptidase-9 levels. Its LD50 > 1000 mg/kg on mice and hERG channel inhibition IC50 > 30 µM, which lower acute toxicity and hERG channel inhibition would make compound 9 a promising stroke treatment candidate.

Discovery of 1,2,4-triazole derivatives as novel neuroprotectants against cerebral ischemic injury by activating antioxidant response element.

Acute ischemic stroke is an important cause of death and long-term disability worldwide. In this work, we have synthesized a series of derivatives with 3,5­diaryl substituent triazole scaffolds. The derivatives showed favorable protective effective in SNP-induced oxidative stress model, of which compound 5 was the most active. In vivo experiments showed that compound 5 could ameliorate neurological deficits, attenuate infarction sizes, reduce malonaldehyde (MDA) level and increase superoxide dismutase (SOD) level in middle cerebral artery occlusion (MCAO) rats. Preliminary safety evaluation showed that compound 5 exhibited low acute toxicity in BALB/c mice (LD50 greater than 1000 mg/kg). Further investigation indicated that compound 5 was able to scavenge ROS, restore mitochondrial membrane potential and protect PC12 cells from SNP-induced apoptosis. Moreover, compound 5 could initiate transcription of antioxidant response element (ARE) and induced expressions of antioxidative enzymes. Collectively, compound 5 might have the potency of treating acute ischemic stroke.

Synthesis and biological evaluation of 1,2,4-triazole derivatives as potential Nrf2 activators for the treatment of cerebral ischemic injury.

Acute ischemic stroke is a leading cause of disability and death. The development of neuroprotectants is an emerging strategy for the treatment of ischemic stroke. In this work, we designed and synthesized a series of 1,3,5-triaryl substituent triazole derivatives by introducing a phenolic group and phenyl ring to 3,5-diaryl substituents oxadiazole. Structure-activity relationship (SAR) analysis showed that compounds with alkyl groups or with substituents at the 3-position possessed better protective effects. Among the derivatives, 3,5-dimethyl substituted compound 24 exhibited the best neuroprotective effect with weak cytotoxicity. Compound 24 possessed a high plasma protein binding rate, moderate hERG inhibition, low acute toxicity, and suitable pharmacokinetic properties. In vivo experiments demonstrated that compound 24 exerted a protective effect by reducing cerebral infarction size, improving neurological behavior, and restoring redox balance in middle cerebral artery occlusion rats. Further investigation indicated that compound 24 exerted a protective effect against sodium nitroprusside (SNP) induced cell damage by scavenging intracellular reactive oxygen species and restoring mitochondrial membrane potential. Moreover, compound 24 induced the nuclear translocation of Nuclear factor erythroid 2-related factor (Nrf2) and promoted the generation of antioxidative proteins, including Heme oxygenase-1 (HO-1), NAD(P)H quinone dehydrogenase (NQO1), and glutamate-cysteine ligase catalytic (GCLC). Surface plasmon resonance (SPR) experiments indicated that compound 24 might activate the Nrf2 signaling pathway by interacting with the Keap1 Kelch domain. Taken together, these facts indicate that compound 24 might have potential in the treatment of ischemic stroke.

Synthesis and biological evaluation of 1,2,4-oxadiazole core derivatives as potential neuroprotectants against acute ischemic stroke.

Here, we report the synthesis and neuroprotective capacity of 27 compounds with a bisphenol hydroxyl-substituted 1,2,4-triazole core or 1,2,4-oxadiazole core for stroke therapy. In vitro studies of the neuroprotective effects of compounds 1-27 on sodium nitroprusside (SNP)-induced apoptosis in PC12 cells indicate that compound 24 is the most effective compound conferring potent protection against oxidative injury. Compound 24 inhibits reactive oxygen species (ROS） accumulation and restores the mitochondrial membrane potential (MMP). Moreover, further analysis of the mechanism showed that compound 24 activates the antioxidant defence system by promoting the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and increasing the expression of haem oxygenase 1 (HO-1). An in vivo study was performed in a rat model of transient focal cerebral ischaemia generated by the intraluminal occlusion of the middle cerebral artery (MCAO). Compound 24 significantly reduced brain infarction and improved neurological function. Overall, compound 24 potentially represents a promising compound for the treatment of stroke.

5-[2-(N-(Substituted phenyl)acetamide)]amino-1,3,4-thiadiazole-2-sulfonamides as Selective Carbonic Anhydrase II Inhibitors with Neuroprotective Effects.

In this study, 22 novel compounds were designed and synthesized by acetamide bridge chains, among which 5 a-5 k were monosubstituted compounds, and 6 a-6 k were disubstituted. A series of biological evaluations was then carried out to determine the carbonic anhydrase inhibitory activity, neuroprotective effects and cytotoxicity of 5 a-5 k and 6 a-6 k. The results showed that some compounds could protect PC12 cells from sodium nitroprusside (SNP)-induced damage. In terms of the neuroprotection and inhibitory activity against carbonic anhydrase II, monosubstituted compounds were better than disubstituted. Compound 5 c exhibited better protective effect in PC12 cells than that of edaravone, and 5 c also showed less cytotoxicity. In addition, compound 5 c was found to be the most effective selective carbonic anhydrase II inhibitor (IC50 =16.7 nM, CAI/CAII=54.3), which was similar to the inhibitory effect of acetazolamide. Moreover, the selectivity of compound 5 c was better than that of acetazolamide (IC50 =12.0 nM, CAI/CAII=20.8). Molecular docking presented that the binding effect of compound 5 c with carbonic anhydrase II was superior to that of 5 c with carbonic anhydrase I and IX, which was consistent with the inhibitory results. Based on above findings, compound 5 c may be a potential candidate for selective carbonic anhydrase II inhibitor, and it had obviously neuroprotective effect and great advantages in drug safety.

Synthesis and biological evaluation of 1,2,4-triazole derivatives as potential neuroprotectant against ischemic brain injury.

A series of 1,2,4-triazole derivatives 1-14 was synthesized to investigate their neuroprotective effects and mechanisms of action. Compounds 5-11 noticeably protected PC12 cells from the cytotoxicity of H2O2 or sodium nitroprusside (SNP). Compound 11 was the most effective derivative. Compound 11 chelated Fe (II) iron, scavenged reactive oxygen species (ROS), and restored the mitochondrial membrane potential (MMP). Moreover, it enhanced the activity of the antioxidant defense system by increasing the serum level of superoxide dismutase (SOD) and promoting the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2). Compound 11 caused certain improvements in behavior, the cerebral infarction area, and serum levels of biochemical indicators (TNF-α, IL-1ß, SOD and MDA) in a rat MCAO model. The lethal dose (LD50) of compound 11 in mice receiving intraperitoneal injections was greater than 400 mg/kg. Meanwhile, pharmacokinetic experiments revealed high bioavailability of this compound after both oral and intravenous administration (F = 60.76%, CL = 0.014 mg/kg/h) and a longer half-life (4.26 and 5.11 h after oral and intravenous administration, respectively). Based on these findings, compound 11 may be a promising neuroprotectant for the treatment of ischemic stroke.