Antioxidative and thrombolytic TMP nitrone for treatment of ischemic stroke

Ischemic stroke results from brain blood vessel blockage by thrombus, and produces neuronal cell damage and death. While thrombolytic therapy with tPA has achieved some success in clinic, the strategy of using neuroprotective agents to treat ischemic stroke has been disappointing thus far. In the present work, we synthesized TBN, a derivative of the clinically useful stroke drug TMP armed with a powerful free radical-scavenging nitrone moiety. TBN retains the thrombolytic activity of the parent TMP and possesses strong antioxidative properties. TBN demonstrates significant activity in the rat MCAo stroke model. The results suggest that design of molecules possessing both thrombolytic and neuroprotective properties may be a novel strategy for effective stroke therapeutics.     

Design, synthesis, and biological activities of novel Ligustrazine derivatives

A series of novel Ligustrazine derivatives was designed, synthesized, and assayed for their protective effects on damaged ECV-304 cells and antiplatelet aggregation activities. The results showed that most Ligustrazine derivatives exhibited lower EC(50) values for protective effects on the ECV-304 cells damaged by hydrogen peroxide in comparison with Ligustrazine. And some Ligustrazine derivatives presented better antiplatelet aggregation activities than Ligustrazine. The derivatives containing the bisphenylmethyl pharmacophore (7a-c) exhibited highest potency. Compound 7a displayed most potential protective effects on the ECV-304 cells damaged by hydrogen peroxide, and compound 7c was found to be the most active antiplatelet aggregation agent. Structure-activity relationships were briefly discussed.     

Ligustrazine derivatives. Part 3: Design,synthesis and evaluation of novel acylpiperazinyl derivatives as potential cerebrocardiac vascular agents

A series of novel acylpiperazinyl Ligustrazine derivatives was designed, synthesized, and their protective effects on damaged ECV-304 cells and antiplatelet aggregation activities were evaluated. The results showed that compound E33 displayed most potential protective effects on the ECV-304 cells damaged by hydrogen peroxide, and compound E1 was found to be the most active antiplatelet aggregation agent. Structure–activity relationships were briefly discussed.     

Antiradical and NO-inhibiting activities of bet-hydroxy(ethoxy) derivatives of nitrous heterocycles

The antiradical and NO-inhibiting activities of beta-hydroxy(ethoxy) derivatives of nitrous heterocycles (3-hydroxypyridine, 5-hydroxybenzimodazole, and 6-hydroxy(alkoxy)-benzothiazole) have been studied. The antiradical activity has been studied using a homogeneous hydrophilic chemiluminescent system, and the quenching constants (Ki) have been determined. For the most reactive compound, 4-methylthiobenzimidazolyl-3-hydroxypyridine, Ki = 4.5 x 105 M(-1). The NO-inhibiting activity was estimated on a model of the endotoxin shock of experimental animals using a spin trap of nitric oxide radicals based on complexes of iron with sodium diethyldithiocarbamate. It was found that the compounds at doses of 0.25-1 mmol/kg have both the inhibitory and stimulating action on the production of nitric oxide in the liver of animals. The results obtained suggest that some derivatives of nitrous heterocycles can be used as effective antioxidant preparations.     

New benzyl pyridinium derivatives bearing 2,4-dioxochroman moiety as potent agents for treatment of Alzheimer’s disease: Design,synthesis, biological evaluation,and docking study

A new series of benzyl pyridinium-2,4-dioxochroman derivatives 7a-o was synthesized and evaluated as new anti-Alzheimer agents. Among the synthesized compounds, the compounds 7f and 7i exhibited the most potent anti-AChE and anti-BuChE activities, respectively. The kinetic study of the compound 7f revealed that this compound inhibited AChE in a mixed-type inhibition mode. Furthermore, the docking study of the compounds 7f and 7i showed that these compounds bound to both the catalytic site (CS) and peripheral anionic site (PAS) of AChE and BuChE, respectively. The compound 7f also exhibited a greater self-induced Aβ peptide aggregation inhibitory activity in compare to donepezil. Furthermore, the neuroprotective activity of this compound at 20 μM was comparable to that of the standard neuroprotective agent (quercetin).     

Design and synthesis of novel senkyunolide analogues as neuroprotective agents

A class of senkyunolide analogues bearing benzofuranone fragment were designed, synthesized and evaluated for their neuroprotective effect in models of oxygen glucose deprivation (OGD) and oxidative stress. All tested compounds showed neuroprotection profile based on the cell viability assay. In particular, derivatives 1f–1i possessing furoxan-based nitric oxide releasing functionality exhibited significant biological activities in OGD models. More importantly, compound 1g containing short linker with furoxan displayed the most potent neuroprotection at the concentration of 100?μM (cell survival up to 145.2%). Besides, 1g also showed the middle level neuroprotective effect in model of oxidative stress.     

Structure-activity relationships of some taxoids as multidrug resistance modulator

1,7-Deoxy-4-deacetylbaccatin III (12) and its five analogues 6-9, 13, and their oxetane ring opened derivatives 14, 16, and 17, which were synthesized from taxinine, showed significant activity as MDR reversal agent by the assay of the calcein accumulation toward MDR human ovarian cancer 2780AD cells. The most effective compound 12 in this assay is actually efficient for the recovery of cytotoxic activity of paclitaxel (taxol), adriamycin (ADM), and vincristine (VCR) toward MDR 2780AD cells at the same level toward parental 2780 cells. This activity of 12 is very interesting because baccatin III (4) has no such MDR reversal activity but has cytotoxic activity. The essential functional groups inducing such a difference in biological activity between 4 and 12 are 4alpha-acetoxyl for 4 and 4alpha-hydroxyl for 12. In seven compounds possessing MDR reversal activity, compound 12 is the most desirable compound for anti-MDR cancer reversal agent, because it has the highest accumulation ability of anticancer agent in MDR cancer cells and weak cytotoxic activity. Compounds 8 and 13 showed significant cytotoxic activity toward HepG2 and VA-13, respectively, as well as MDR reversal activity. They are expected to become lead compounds for new types of anticancer agent or anti-MDR cancer agent.     

Synthesis and anticonvulsant activity of aromatic tetramethylcyclopropanecarboxamide derivatives

As part of our ongoing research on potential new antiepileptic drugs (AEDs), a series of tetramethylcyclopropanecarboxamide derivatives containing benzene ring were designed, synthesized, and evaluated for anticonvulsant activities in the murine maximal electroshock (MES) and subcutaneous pentylenetetrazole (scMet) seizure tests. The most potent compound emerging from this study was N-(2,2,3,3-tetramethylcyclopropanecarboxamide)-p-phenyl-sulfonamide (21), possessing an ED(50) value of 26mg/kg in the rat-MES test and a remarkable PI (PI=TD(50)/ED(50)) value above 19. The better anticonvulsant potency of compound 21 and its wider safety margin compared to valproic acid (VPA) and zonisamide make it a potential candidate to become a new AED second-generation to VPA.     

Direct semi-synthesis of the anticancer lead-drug protoapigenone from apigenin, and synthesis of further new cytotoxic protoflavone derivatives

Protoapigenone, a natural flavonoid possessing an unusual p-quinol moiety on its B-ring, is a novel prospective anticancer agent with low toxicity that is currently in development. The first economical, one-step synthesis of protoapigenone from apigenin is described on up to gram scale. 13 new 1'-O-alkylflavone analogs were also synthesized, either from apigenin or β-naphthoflavone. The in vitro cytotoxic activity of each compound was tested on six human cancer cell lines (HepG2, Hep3B, Ca9-22, A549, MCF-7 and MDA-MB-231). In the case of 1'-O-alkyl-protoapigenone derivatives, structure-activity relationships were found depending on the side-chain, and protoapigenone 1'-O-butyl ether was found to exert significantly stronger activity against three of the cell lines (Hep3B, MCF-7 and MDA-MB-231) than its non-substituted analog, protoapigenone itself. In contrast to this, all β-naphthoflavone derivatives bearing the same pharmacophore on their B-ring showed decreased cytotoxic activities when substituted with an O-alkyl side-chain at position 1', comparing to that of the non-substituted compound.     

Stroke pathophysiology: management challenges and new treatment advances

Stroke is the second leading cause of death and the first cause of lost disability-adjusted years in developed countries. During the past decade, new developments in thrombolytic therapy have led to the implementation of emergency intervention protocols for the treatment of ischemic stroke, replacing the widespread sense of therapeutic nihilism in the past. Treatment with rtPA has shown to be effective within the first 3 hours following stroke onset and the FDA and the European Medical Agency (EMEA) have approved its use. Acknowledging the urgency and intricacies of stroke, Stroke Units allow the monitoring of physiological parameters in the acute phase of stroke and are considered an important management tool that can significantly improve the quality of care provided to the patient. The concept of neuroprotective therapy for acute ischemic stroke to salvage tissue at risk and improve functional outcome is based on sound scientific principles and extensive preclinical animal studies demonstrating efficacy. However, most neuroprotective drugs in clinical trials have failed, possibly due to inadequate preclinical testing or flawed clinical development programs. Several new treatment strategies are under development and are being tested. This review is directed at understanding the management of acute ischemic stroke pathophysiology. We address the management challenges and new treatment advances by integrating the knowledge of possible pharmacological targets for acute ischemic stroke. We hope to shed new light upon the controversy surrounding the management of acute ischemic stroke in an attempt to elucidate why failed clinical trials continue to occur despite promising neuroprotective preclinical studies.     

Synthesis of Novel 3-Butylphthalide Derivatives Containing Isopentenylphenol Moiety as Potential Antiplatelet Agents for the Treatment of Ischemic Stroke

In order to find novel antiplatelet drugs for the treatment of ischemic stroke, a series of 3-butylphthalide derivatives containing isopentenylphenol moiety were designed, synthesized and characterized with spectroscopic analyses. The in vitro antiplatelet activity results indicated that compound 3 better inhibited the arachidonic acid (AA) induced platelet aggregation than aspirin (ASP) and 3-butylphthalide (NBP). Additionally, compared with precursor NBP, compound 3 possessed outstanding antithrombotic activity in the animal experiment model, which could effectively alleviate the formation of tail thrombus and carotid artery thrombus in mice. More importantly, intraperitoneal administration of compound 3 can well protected the rats against ischemia/reperfusion-induced brain injury. Further pharmacokinetic (PK) assay indicated that compound 3 had good absorption characteristics and metabolic stability in vivo. Overall, the present research provides a new candidate compound for the treatment of ischemic stroke caused by platelet aggregation.     

Antiradical and NO-Inhibiting activities of β-hydroxy(ethoxy) derivatives of nitrous heterocycles

The antiradical and NO-inhibiting activities of β-hydroxy(ethoxy) derivatives of nitrous heterocycles (3-hydroxypyridine, 5-hydroxybenzimodazole, and 6-hydroxy(alkoxy)-benzothiazole) have been studied. The antiradical activity has been studied using a homogeneous hydrophilic chemiluminescent system, and the quenching constants (K _i ) have been determined. For the most reactive compound, 4-methylthiobenzimidazolyl-3-hydroxypyridine, K _i = 4.5 × 10⁵ M⁻¹. The NO-inhibiting activity was estimated on a model of the endotoxin shock of experimental animals using a spin trap of nitric oxide radicals based on complexes of iron with sodium diethyldithiocarbamate. It was found that the compounds at doses of 0.25–1 mmol/kg have both the inhibitory and stimulating action on the production of nitric oxide in the liver of animals. The results obtained suggest that some derivatives of nitrous heterocycles can be used as effective antioxidant preparations.     

Synthesis of plaunotol derivatives and their antibacterial activities against Helicobacter pylori.

Plaunotol, a known antiulcer drug, has antibacterial activities against Helicobacter pylori. Plaunotol thiourea derivatives 2--4 and diol derivatives 6--10 were designed in search for a compound with high antibacterial activities. Thiourea derivatives 2--4 were synthesized regioselectively using our effective synthetic route for plaunotol (1), and diol derivatives 6--10 were also synthesized. Their antibacterial activities against H. pylori are described and we found that the most potent antibacterial agent was C1-thiourea derivative 2c.     

Synthesis,structural characterization and in vivo anti-diabetic evaluation of some new sulfonylurea derivatives in normal and silicate coated nanoparticle forms as anti-hyperglycemic agents

Series of new sulfonylurea derivatives (gliclazide analogues) was synthesized and characterized. Thus, p-tolylsulfonylisocyanate was left to react with different amino derivatives under mild conditions to afford the desired sulfonylurea derivatives 1–5. The molecular structure of the compound N-(2,6-Dichlorophenylcarbamoyl)-4-methylbenzenesulfonamide, 1c has been elucidated by single crystal X-ray diffraction. Anti-diabetic properties of the synthesized compounds relative to anti-diabetic drug (gliclazidem MR60) were carried out, where most of the tested compounds showed significant activity for reducing the blood glucose level. The results revealed that compounds 1c and 5 showed better anti-diabetic activities compared with gliclazide. Activity of the most potent derivatives of sulfonylurea compounds namely 1c and 5 were increased using coated nanostructure tetraethyl orthosilicate (TEOS) as a modified release (MR) agent. The effect of the prepared sulfonylurea compounds against the diabetic condition was investigated using specific selected biomarkers as of liver enzyme activities as transaminases (AST, ALT) and alkaline phosphatase (ALP), lipids profiles; total cholesterol (TC), triacylglycerols (TG) and total lipid (TL). The antioxidants, oxidative stress biomarkers and histological examination were also examined and discussed.     

Synthesis and neuroprotective effect of E-3,4-dihydroxy styryl aralkyl ketones derivatives against oxidative stress and inflammation

E-3,4-Dihydroxy styryl aralkyl ketones as well as their 3,4-diacetylated derivatives as the analogues of neuroprotective agent CAPE were designed and synthesized for improving stability and lipid solubility. The neuroprotective activities of target compounds 10a–g and 11a–g were tested by three models in vitro, including 1,1-diphenyl-2-picrylhydrazyl radical scavenging capacity, neuronal protecting effect against damage induced by H₂O₂ in PC12 cells and nitric oxide suppression effect in BV2 microglial cells. The results demonstrated that compounds 10f and 11f exhibited the most potent neuroprotective effect against oxidative stress and inflammation, which is higher than that of the lead compound CAPE.     

Activated protein C inhibits tissue plasminogen activator-induced brain hemorrhage

Brain hemorrhage is a serious complication of tissue plasminogen activator (tPA) therapy for ischemic stroke. Here we report that activated protein C (APC), a plasma serine protease with systemic anticoagulant, anti-inflammatory and antiapoptotic activities, and direct vasculoprotective and neuroprotective activities, blocks tPA-mediated brain hemorrhage after transient brain ischemia and embolic stroke in rodents. We show that APC inhibits a pro-hemorrhagic tPA-induced, NF-kappaB-dependent matrix metalloproteinase-9 pathway in ischemic brain endothelium in vivo and in vitro by acting through protease-activated receptor 1. The present findings suggest that APC may improve thrombolytic therapy for stroke, in part, by reducing tPA-mediated hemorrhage.     

Design,synthesis, and biological evaluation of selective and potent Carbazole-based butyrylcholinesterase inhibitors

Alzheimer’s disease (AD) is the most common form of dementia. Inhibition of BChE might be a useful therapeutic target for AD. A new series of Carbazole-Benzyl Pyridine derivatives were designed synthesized and evaluated as butyrylcholinesterase (BChE) inhibitors. In vitro assay revealed that all of the derivatives had selective and potent anti- BChE activities. 3-((9H-Carbazol-9-yl)methyl)-1-(4-chlorobenzyl)pyridin-1-ium chloride (compound 8f) had the most potent anti-BChE activity (IC₅₀ value?=?0.073?μM), the highest BChE selectivity and mixed-type inhibition. Docking study revealed that 8f interacted with the peripheral site, the choline binding site, catalytic site and the acyl pocket of BChE. Physicochemical properties were accurate to Lipinski's rule. In addition, compound 8f demonstrated neuroprotective activity at 10?µM. This compound could also inhibit AChE-induced and self-induced Aβ peptide aggregation at concentration of 100?µM and 10?µM respectively. The in-vivo study showed that compound 8f in 10?mg/kg increased the time spent in target quadrant in the probe day and decreased mean training period scape latency in rats. All results suggest that new sets of potent selective inhibitors of BChE have a therapeutic potential for the treatment of AD.     

Synthesis and biological evaluation of N-arylpiperazine derivatives of 4,4-dimethylisoquinoline-1,3(2H,4H)-dione as potential antiplatelet agents

Despite the substantial clinical success of aspirin and clopidogrel in secondary prevention of ischemic stroke, up to 40% of patients remain resistant to the available antiplatelet treatment. Therefore, there is an urgent clinical need to develop novel antiplatelet agents with a novel mechanism of action. Recent studies revealed that potent alpha 2B-adrenergic receptor (alpha 2B-ARs) antagonists could constitute alternative antiplatelet therapy. We have synthesized a series of N-arylpiperazine derivatives of 4,4-dimethylisoquinoline-1,3(2H,4H)-dione as potential alpha 2B receptor antagonists. The most potent compound 3, effectively inhibited the platelet-aggregation induced both by collagen and ADP/adrenaline with IC₅₀ of 26.9?μM and 20.5?μM respectively. Our study confirmed that the alpha 2B-AR antagonists remain an interesting target for the development of novel antiplatelet agents with an alternative mechanism of action.     

Synthesis of phenanthroindolizidine alkaloids and evaluation of their antitumor activities and toxicities

We previously reported that phenanthroindolizidine alkaloid 3 and its derivatives had markedly potent in vitro cytotoxicity. However, they had low in vivo antitumor activities and high in vivo toxicities, which was a serious problem. To address this problem, new phenanthroindolizidine derivatives were synthesized and their antitumor activities and toxicities were evaluated. This study describes the relationship between the chemical structures, antitumor activities, and toxicities of these phenanthroindolizidine derivatives. Based on its properties, compound 8 was found to be the most suitable potential antitumor agent.     

2-Benzoylbenzofuran derivatives possessing piperazine linker as anticancer agents

A series of novel 2-benzoylbenzofuran derivatives possessing piperazine linker have been prepared, and their in vitro anticancer activity against a panel of human tumor cell lines by MTT assay were evaluated. The results demonstrated that tertiary amine derivatives exhibited better cytotoxic activity, and SAR study revealed that electron-donating substituents on the phenyl ring of the derivatization functionality contributed to potent anticancer activities. Among them, compounds 6, 9, 11, 18, 23 and 25 displayed both better anti-tumor activity and lower cytotoxic effect on human normal liver cell L02. Further apoptosis analysis showed that compound 18 significantly induced apoptosis in A549 cell, which was considered as the most potent anticancer agent.