3‐butyl‐6‐fluoro‐1(3H)‐isobenzofuranone (6‐F‐NBP), a derivative of dl‐n‐butylphthalide,inhibits glutamate‐induced cytotoxicity in PC12 cells

It is widely recognized that glutamate (Glu)‐induced cytotoxicity, intracellular calcium overload and the excessive free radical production are key events in the development and progression of ischemic brain injury. dl‐3‐n‐butylphthalide (NBP), an anti‐ischemic agent, has therapeutic effects in animal models of vascular dementia. The aim of the present study was to investigate the protective effect of 3‐butyl‐6‐fluoro‐1(3H)‐isobenzofuranone (6‐F‐NBP), a derivative of NBP on Glu‐induced cytotoxicity in rat pheochromocytoma (PC12) cells, and to compare this action with NBP. The results showed that after 24‐h incubation with Glu (5 mM), cell viability and mitochondrial membrane potential (MMP) were decreased. In contrast, the content of reactive oxygen species (ROS), activity of nitric oxide synthase (NOS), and apoptosis rate, as well as intracellular accumulation of [Ca²⁺]_i, were increased, 6‐F‐NBP inhibited the damage induced by Glu in a dose‐dependent manner and exerted a more potent effect than NBP, indicating that 6‐F‐NBP exhibited a protective effect against Glu‐induced cytotoxicity in cultured PC12 cells. Drug Dev Res 73: 11–17, 2012. © 2011 Wiley Periodicals, Inc.     

Protective effect of CPUX1, a progesterone,on hydrogen peroxide‐induced oxidative damage in PC12 cells

The protective effect of CPUX1, a novel progesterone analog, on hydrogen peroxide (H₂O₂)‐induced oxidative damage was investigated in rat pheochromocytoma (PC12) cells. Following the exposure of PC12 cells to H₂O₂, there was a reduction in cell survival and activities of superoxide dismutase (SOD) and mitochondrial membrane potential (MMP) accompanied by increased levels of lactate dehydrogenase (LDH) release, malondialdehyde (MDA) production, and intracellular reactive oxygen species (ROS) and intracellular [Ca²⁺]i levels. Preincubation of cells with CPUX1 prior to H₂O₂ exposure attenuated all these changes mentioned and had a protective effect against H₂O₂‐induced toxicity in PC12 cells, indicating that the compound may have potential therapeutic benefit for CNS disorders influenced by oxidative damage. Drug Dev Res 69: 2008 ©2008 Wiley‐Liss, Inc.     

Effects of 2‐(1‐hydroxypentyl)‐benzoate on platelet aggregation and thrombus formation in rats

2‐(1‐hydroxypentyl)‐benzoate (dl‐PHPB), a derivate of 3‐n‐butylphthalide (NBP), is a novel therapeutic agent for treatment of cerebral ischemia. In the present study, the antiplatelet and antithrombotic activities of dl‐PHPB were evaluated in ex vivo platelet aggregation and in vivo arteriovenous (A‐V) shunt models. dl‐PHPB inhibited platelet aggregation induced by adenosine diphosphate (ADP), arachidonic acid (AA), and collagen (COL) in a dose‐dependent manner when given orally (12.9–129.5 mg/kg). The inhibitory potency was similar to 3‐n‐butylphthalide (NBP) and aspirin (ASP). Inhibition on platelet aggregation was also observed after iv administration of dl‐PHPB (1.29–12.9 mg/kg). The time‐course of these effects showed the maximal inhibition on platelet aggregation at 1 h after oral administration and 30 min after iv injection. dl‐PHPB (12.9–129.5 mg/kg, p.o.) caused dose‐dependent inhibition of thrombus formation in the rat A‐V shunt thrombosis model. These results show that dl‐PHPB is an orally and iv antiplatelet and antithrombotic agent and may be useful for treatment of ischemia stroke. Drug Dev Res 63:174–180, (2004). © 2004 Wiley‐Liss, Inc.     

Novel 19F‐MRS β‐galactosidase reporter molecules incorporated nitrogen mustard analogues

In this study, we propose a novel molecular platform‐integrated fluorinated antitumor nitrogen mustards for ¹⁹F‐MRS assay of β‐galactosidase (β‐gal) activity. Following this idea, we have designed, synthesized, and characterized 2‐fluoro‐4‐[bis(2′‐chloroethyl)amino]phenyl β‐D‐galactopyranoside 5 , 2‐fluoro‐4‐{bis[2′‐O‐(β‐D‐galactopyranosyl)ethyl]amino}phenyl β‐D‐galactopyranoside 8 , 2‐fluoro‐4‐{bis[[1″‐(β‐D‐galactopyranosyl)‐1″, 2″, 3″‐triazol‐4″‐yl]methyl] amino}phenyl β‐D‐galactopyranoside 14 and 2‐fluoro‐4‐{bis[[1″‐(β‐D‐glucopyranosyl)‐1″, 2″, 3″‐triazol‐4″‐yl]methyl]amino}phenyl β‐D‐galactopyranoside 15 through glycosylation and click reaction strategies, and their structures were confirmed by NMR and HRMS or elemental analysis data. Among them, 2‐fluoro‐4‐[bis(2′‐chloroethyl)amino]phenyl β‐D‐galacto‐pyranoside 5 was found very sensitive to β‐gal (E801A) in PBS at 37°C with big Δδ_F response. Here, we demonstrated the feasibility of this platform for assessing β‐gal activity in solution, and in vitro with lacZ‐transfected human MCF7 breast and PC3 prostate tumor cells, by the characterization of β‐gal‐responsive ¹⁹F‐chemical shift changes Δδ_F and hydrolytic kinetics.     

Synthesis of deuterium‐labeled 3‐O‐methyldopa and 4‐O‐methyldopa

Concise methods for the synthesis of 4‐hydroxy‐3‐[²H₃]‐methoxyphenylalanine (3‐O‐[²H₃]‐methydopa) and 3‐hydroxy‐4‐[²H₃]‐methoxyphenylalanine (4‐O‐[²H₃]‐methydopa) are described. The 3‐O‐[²H₃]‐methydopa is a valuable internal standard for the tandem MS quantification of 3‐O‐methyldopa, a metabolite of value in the diagnosis of aromatic l‐amino acid decarboxylase (AADC) deficiency. Copyright © 2003 John Wiley & Sons, Ltd.     

Protective effects of 1,3‐diaryl‐2‐propen‐1‐one derivatives against H2O2‐induced damage in SK‐N‐MC cells

Alzheimer's disease (AD) is an age‐related neurodegenerative disorder of the central nervous system resulting in memory loss and dementia. Some of the associated pathogenic changes are amyloid peptide aggregation, excitotoxicity, oxidative stress and inflammation. Oxidative stress plays an indispensable role in the pathophysiology of AD. Therefore, antioxidant therapies appear to be promising approaches in dealing with AD patients. In that line, we evaluated the free radical scavenging capabilities of 13 different chalcones (1,3‐diphenyl‐2‐propen‐1‐one) derivatives against the free‐radical damaging effects of hydrogen peroxide (H₂O₂) on the SK‐N‐MC neuroblastoma cell line. Pretreatment of the cells for 3 h with 20 µ m of each of these derivatives (compounds 8 – 20 ) followed by exposure to 300 µ m H₂O₂ for 24 h indicated that all compounds, except compound 20 , were capable of restoring the viabilities of cells relative to the control (H₂O₂–treated) cells. The destructive effect of H₂O₂ on the adhesive behavior of the cells was almost totally restored by each of the derivatives. In addition, each of the derivatives except compounds 20 and 14 significantly reduced the extent of lipofuscin formation among the cells time‐dependently. Despite these activities, some of the derivatives, such as compounds 12 and 19 , did not reduce the H₂O₂‐induced intracellular ROS (reactive oxygen species) levels, meaning that these two derivatives act through a different mechanism other than free‐radical scavenging activity. On the other hand, for those derivatives acting as anti‐oxidants, structure–activity evaluation clearly revealed that the hydroxyl group of vanillin ring is required for their free‐radical scavenging activities. Copyright © 2010 John Wiley & Sons, Ltd.     

Synthesis of 3H and 14C labeled (S)‐3‐(5‐chloro‐2‐methoxyphenyl)‐1,3‐dihydro‐3‐fluoro‐6‐(trifluoromethyl)‐2H‐indol‐2‐one,maxipost™. An agent for post‐stroke neuroprotection

The syntheses of tritium labeled (S)‐3‐(5‐chloro‐2‐[OC³H₃]methoxyphenyl‐1,3‐dihydro‐3‐fluoro‐6‐(trifluoromethyl)‐1H‐indol‐2‐one, and carbon‐14 (S)‐3‐(5‐chloro‐2‐methoxyphenyl)‐1,3‐dihydro‐3‐fluoro‐6‐(trifluoromethyl)‐2H‐[2,3‐¹⁴C₂] indol‐2‐one are reported. The ³H‐labeled compound was prepared in a two‐step synthesis from C³H₃I. The final product was purified via chiral HPLC to yield the desired enantiomer in a 4% radiochemical yield and a specific activity of 60 Ci/mmol. The ¹⁴C‐labeled compound was prepared in a four‐step synthesis from diethyl [carboxylate‐¹⁴C₁,₂] oxalate. The final product was purified via chiral HPLC to yield the desired enantiomer in a 20% radiochemical yield and a specific activity of 28.4 μCi/mg. Copyright © 2002 John Wiley & Sons, Ltd.     

Synthesis and Protective Effects of Kaempferol‐3′‐sulfonate on Hydrogen Peroxide‐induced injury in Vascular Smooth Muscle Cells

A novel water‐soluble sulfated derivative, kaempferol‐3′‐sulfonate acid sodium (KS) with the composition of [C₁₅H₉O₉SNa]·2.5H₂O, was synthesized and characterized by elemental analysis, IR, ¹H NMR, ¹³C NMR, and HRMS. Its protective effects on human vascular smooth muscle cells injured by hydrogen peroxide were evaluated by CCK‐8 method, flow cytometry, and Western blotting. The experimental results indicated that the KS can significantly increase cell viability and reduce apoptosis on H₂O₂‐injured VSMCs, as well as reverse the effects of H₂O₂ on Bcl‐2, Bad, and caspase‐3 expressions. In addition, LDH leakage, MDA levels, and SOD and GSH activities were also measured with spectrophotometry. The results indicated that the KS acted as antioxidant preventing LDH leakage and MDA production, while increasing intracellular SOD and GSH activities. These findings revealed that KS might potentially serve as an effective antioxidant agent for prevention and treatment of vascular disease caused by H₂O₂‐injured VSMCs.     

7‐difluoromethyl‐5,4′‐dimethoxygenistein,a novel agent protecting against vascular endothelial injury caused by oxidative stress

1. Genistein is known to protect the vascular endothelium. However, genistein exhibits poor bioavailability, which limits its use in the treatment of cardiovascular diseases. 7‐Difluoromethyl‐5,4′‐dimethoxygenistein (dFMGEN), prepared by the difluoromethylation and alkylation of genistein, is a new active chemical entity. The protective effects of dFMGEN against vascular endothelial injury caused by oxidative stress were investigated in the present study. 2. Human umbilical vein endothelial cells were treated with either genistein (10 μmol/L) or various concentrations of dFMGEN (0.1, 0.3, 1, 3 and 10 μmol/L) for 30 min before exposure to 1 mmol/L H₂O₂ for 24 h. The generation of reactive oxygen species (ROS) was assessed by fluorescence flow cytometry, the release of lactate dehydrogenase (LDH) was examined by biochemical assay, cell viability was measured by the 3‐(4,5‐dimethyl‐2 thiazoyl)‐2,5‐diphenyl‐2H‐tetrazolium bromide assay, cell apoptosis was detected by flow cytometry and the expression of caspase 3 was examined by western blot analysis. 3. Pretreatment with 0.1, 0.3, 1, 3 and 10 μmol/L dFMGEN decreased the generation of ROS and the release of LDH in H₂O₂‐exposed vascular endothelial cells, enhanced cell viability in a concentration‐dependent manner over the concentration range 0.1–10 μmol/L, suppressed H₂O₂‐induced apoptosis of vascular endothelial cells and downregulated the expression of caspase 3. The protective effect of 10 μmol/L dFMGEN against oxidative stress‐induced endothelial injury was stronger than that of 10 μmol/L genistein. 4. The results of the present study suggest that dFMGEN can protect against vascular endothelial injury caused by oxidative stress.     

The Effect of Tetramethylpyrazine on Hydrogen Peroxide‐Induced Oxidative Damage in Human Umbilical Vein Endothelial Cells

Abstract: Tetramethylpyrazine has been widely used in traditional Chinese medicine to treat cardiovascular diseases such as atherosclerosis and hypertension. The underlying mechanism of cardioprotective effects, however, remains to be elucidated. Here, using human umbilical vein endothelial cells (HUVECs), we have assessed the protective effect of tetramethylpyrazine on H₂O₂‐induced oxidative damage. After pre‐incubation with tetramethylpyrazine (50, 100 and 150 μg/ml) for 24 hr., viability loss in H₂O₂‐induced HUVECs (76.5% of the control level, p < 0.05, at 400 μM of H₂O₂ for 12 hr.) was restored in a concentration‐dependent manner, and the maximal recovery (88.7% of the control level, p < 0.05) was achieved with tetramethylpyrazine at 150 μg/ml. The production of reactive oxygen species was suppressed by measuring fluorescent intensity of 2′,7′‐dichorofluorescein (83.1% of the H₂O₂‐treated group, p < 0.05, at 150 μg/ml of tetramethylpyrazine). Tetramethylpyrazine also increased activities of superoxide dismutase and glutathione peroxidase (144.1% and 118.3% of the H₂O₂‐treated group, respectively, p < 0.05, at 150 μg/ml of tetramethylpyrazine). In addition, tetramethylpyrazine reduced levels of malonaldehyde, intracellular nitric oxide and nitric oxide synthase (83.8%, 91.2% and 78.7% of the H₂O₂‐treated group, respectively, p < 0.05, at 150 μg/ml of tetramethylpyrazine). Furthermore, pre‐incubation of tetramethylpyrazine with HUVECs for 24 hr. resulted in reduction of apoptosis and removal of cell cycle arrest in the S phase (56.6% and 59.7% of the H₂O₂‐treated group, respectively, p < 0.01, at 150 μg/ml of tetramethylpyrazine). Altogether, these results suggest that tetramethylpyrazine has a protective effect on H₂O₂‐induced oxidative damage in HUVECs due to its antioxidant and antiapoptotic properties.     

Reduction by Tetrahydrobiopterin of H2O2–Induced Endothelial Cell Injury

Abstract: The purpose of this study was to examine the effect of tetrahydrobiopterin, a co–factor of nitric oxide synthase, on H₂O₂–induced endothelial cell injury. Pretreatment with sepiapterin, a precursor of tetrahydrobiopterin biosynthesis, increased tetrahydrobiopterin content of endothelial cells, and reduced H₂O₂–induced endothelial cell injury, which was measured by leakage of lactate dehydrogenase. Both the increase in tetrahydrobiopterin content and the protective effect of sepiapterin were prevented by co–pretreatment with N–acetylserotonin, an inhibitor of sepiapterin reductase. Although Ca²⁺ ionophore ionomycin–induccd nitric oxide synthesis was increased by pretreatment with sepiapterin, the protective effect of sepiapterin was not affected by an inhibitor of nitric oxide synthesis. On the other hand, pretreatment with sepiapterin also reduced H₂O₂–induced rat foetal lung fibroblast cell injury via an increase in tetrahydrobiopterin content, despite rat foetal lung fibroblast cells lacking nitric oxide synthase. Moreover, increase in tetrahydrobiopterin strongly reduced H₂O₂–induced intracellular oxidative stress. These findings indicate that sepiapterin reduces H₂O₂–induced endothelial cell injury via an increase in tetrahydrobiopterin content. Although increase in endothelial tetrahydrobiopterin content stimulated nitric oxide production, the protective effect of tetrahydrobiopterin against H₂O₂–induced endothelial cell injury is unlikely to be related to the stimulation of nitric oxide release from nitric oxide synthase. The protective effect of tetrahydrobiopterin may involve reactive oxygen species–scavenging activity.     

Inhibition of ALDH2 protects PC12 cells against formaldehyde‐induced cytotoxicity: involving the protection of hydrogen sulphide

Formaldehyde (FA), a common environmental contaminant, has toxic effects on the central nervous system (CNS). We have previously found that hydrogen sulphide (H₂S), the third endogenous gaseous mediator, protects neuron against the toxicity of FA. However, the underlying mechanism is poor. Aldehyde‐dehydrogenase‐2 (ALDH2) plays a major role in detoxification of reactive aldehyde in a range of organs and cell types. Therefore, we speculated that H₂S antagonizes FA‐induced neurotoxicity by modulating ALDH2. In the present study, we found that the exposure of PC12 cells to FA causes increase in ALDH2 expression and activity. Daidzin, an inhibitor of ALDH2, significantly antagonizes FA‐exerted cytotoxicity and oxidative stress including the accumulation of intracellular reactive oxygen species (ROS), 4‐hydroxy‐2‐trans‐nonenal (4‐HNE), and malondialdehyde (MDA), in PC12 cells. We also showed that daidzin markedly attenuated FA‐induced apoptosis in PC12 cells. Furthermore, we found that H₂S reverses FA‐elicited upregulation of ALDH2 in PC12 cells. Our results demonstrated the involvement of downregulation of ALDH2 in the protection of H₂S against FA neurotoxicity.     

Synthesis and Anti‐neuroinflammatory Activity of Lactone Benzoyl Hydrazine and 2‐nitro‐1‐phenyl‐1H‐Indole Derivatives as p38α MAPK Inhibitors

Inhibition of p38 mitogen‐activated protein kinases (MAPKs) would allow significant modulation of the neuroinflammation condition associated with Alzheimer's disease (AD). Inspired from the pharmacophore of natural NF‐κB and p38α MAPK inhibitor 5,6‐dehydrokawain and p38α MAPK inhibitors 1a, 1‐pyrazolyl‐3‐(4‐((2‐anilinopyrimidin‐4‐yl)oxy)napththalen‐1‐yl)ureas, and 1b , a class of indole–pyrimidinyl compounds which were patented respectively, we designed, de novo synthesized, and evaluated two kinds of novel series of lactone benzoyl hydrazine derivatives and 2‐nitro‐1‐phenyl‐1H‐indole derivatives in an effort to develop pharmacologically tractable agents to alleviate the progression of AD. Fourteen of the seventeen synthesized compounds exhibit significant inhibitory effect on the nitric oxide (NO) production induced by lipopolysaccharide (LPS)‐induced microglia activation with IC₅₀ less than the control 5,6‐dehydrokawain. Notably, compound 27 , 6‐methoxy‐2‐nitro‐1‐(1H‐1, 2, 3‐triazol‐1‐yl)‐1H‐indole, with IC₅₀ values of 1.6  μ m can markedly inhibit p38 α MAPK and NO release in BV‐2 microglial cells. The molecular dynamic (MD) simulations demonstrate that compound 27 inhibits p38 α MAPK through binding to the Glu71 and Asp168 residues. Moreover, in vitro study shows that all compounds can easily cross the blood–brain barrier (BBB) and did not exhibit any acute cellular toxicity checked by MTT assay. These investigations provide promising chemical lead candidate as anti‐neuroinflammatory agents for AD.     

Tris (1,3‐dichloro‐2‐propyl) phosphate induces toxicity by stimulating CaMK2 in PC12 cells

Tris (1,3‐dichloro‐2‐propyl) phosphate (TDCIPP) is one of the widely used organophosphorus flame retardants (OPFRs), which are regarded as suitable substitutes for brominated flame retardants (BFRs). Previously, we have validated the toxicity of TDCIPP in PC12 cells owing to the induced alterations in GAP43, NF‐H, CaMK2a/2b, and tubulin α/β proteins; however, limited information is currently available on the toxicity and mechanism of TDCIPP. In the present study, cytotoxicity effects were evaluated by exposing PC12 cells to different concentrations of TDCIPP (0–50 μM) for 4 days. To explore the possible mechanisms through which cytotoxicity is induced, changes in intracellular [Ca²⁺]_i levels and the activation of calmodulin dependent protein kinase 2 (CaMK2), c‐Jun N‐terminal kinase (JNK), extracellular regulated protein kinases (ERK1/2), and p38 mitogen‐activated protein kinases (MAPK) pathways were evaluated. Furthermore, PC12 cells were pretreated with CaMK2 inhibitor KN93 to investigate the relationship between TDCIPP‐induced phosphorylation of CaMK2 and activation of JNK, ERK1/2, and p38 MAPK pathways. Our results indicate that TDCIPP‐induced toxicity might be associated with the overload of [Ca²⁺]_i levels, increased phosphorylation of CaMK2, and activation of the JNK, ERK1/2, and p38 MAPK pathways, the lattermost of which was further demonstrated to be partially elicited by the CaMK2 phosphorylation.     

Semiquinone fraction isolated from Bacillus sp. INM‐1 protects hepatic tissues against γ‐radiation induced toxicity

Present study was focused on evaluation of a semiquinone glucoside derivative (SQGD) isolated from radioresistant bacterium Bacillus sp. INM‐1 for its ability against γ radiation induced oxidative stress in irradiated mice. Animals were divided into four group, i.e., (i) untreated control mice; (ii) SQGD treated (50 mg/kg b. wt. i.p.) mice; (iii) irradiated (10 Gy) mice; and (iv) irradiated mice which were pre‐treated (?2 h) with SQGD (50 mg/kg b. wt. i.p.). Following treatment, liver homogenates of the treated mice were subjected to endogenous antioxidant enzymes estimation. Result indicated that SQGD pre‐treatment, significantly (P < 0.05) induced superoxide dismutase (SOD) (19.84 ± 2.18% at 72 h), catalase (CAT) (26.47 ± 3.11% at 12 h), glutathione (33.81 ± 1.99% at 24 h), and glutathione‐S‐transferase (24.40 ± 2.65% at 6 h) activities in the liver of mice as compared with untreated control. Significant (P < 0.05) induction in SOD (50.04 ± 5.59% at 12 h), CAT (62.22 ± 7.50 at 72 h), glutathione (42.92 ± 2.28% at 24 h), and glutathione‐S‐transferase (46.65 ± 3.25 at 12 h) was observed in irradiated mice which were pre‐treated with SQGD compared with only irradiated mice. Further, significant induction in ABTS⁺ radicals (directly proportional to decrease mM Trolox equivalent) was observed in liver homogenate of H₂O₂ treated mice which were found to be significantly inhibited in H₂O₂ treated mice pre‐treated with SQGD. Thus, it can be concluded that SQGD treatment neutralizes oxidative stress caused by irradiation not only by enhancing endogenous antioxidant enzymes but also by improving total antioxidant status of cellular system and thus cumulative effect of the phenomenon may contributes to radioprotection. © 2013 Wiley Periodicals, Inc. Environ Toxicol 29: 1471–1478, 2014.     

丁基苯酞对氯化钾和去甲肾上腺素引起的离体大鼠尾动脉环收缩的影响

丁基苯酞(NBP)对脑缺血损伤有保护作用, 为探讨其作用机制, 采用离体大鼠尾动脉环为标本, 观察了NBP对KCl和去甲肾上腺素所致尾动脉收缩的影响, 以及NBP与细胞内, 外钙的关系. 结果表明：NBP在大剂量时，能非竞争性及竞争性地抑制KCl及去甲肾上腺素引起的血管收缩. pD’₂及pA₂值分别为3.57±0.14及4.86±0.13，表明作用较弱. NBP 100 μmol·L^-1对去甲肾上腺素 的内源性钙收缩有抑制作用，而对外源性钙收缩无影响. 说明NBP抑制内钙释放作用比对外钙的阻断作用强.     

Synthesis,In Vitro Protoporphyrinogen Oxidase Inhibition,and Herbicidal Activity of N‐(Benzothiazol‐5‐yl)hexahydro‐1H‐isoindole‐1,3‐diones and N‐(Benzothiazol‐5‐yl)hexahydro‐1H‐isoindol‐1‐ones

Protoporphyrinogen oxidase ( EC 1.3.3.4 ) is one of the most significant targets for a large family of herbicides. As part of our continuous efforts to search for novel protoporphyrinogen oxidase‐inhibiting herbicides, N‐(benzothiazol‐5‐yl)tetrahydroisoindole‐1,3‐dione was selected as a lead compound for structural optimization, leading to the syntheses of a series of novel N‐(benzothiazol‐5‐yl)hexahydro‐1H‐isoindole‐1,3‐diones ( 1a – o ) and N‐(benzothiazol‐5‐yl)hexahydro‐1H‐isoindol‐1‐ones ( 2a – i ). These newly prepared compounds were characterized by elemental analyses, ¹H NMR, and ESI‐MS, and the structures of 1h and 2h were further confirmed by X‐ray diffraction analyses. The bioassays indicated that some compounds displayed comparable or higher protoporphyrinogen oxidase inhibition activities in comparison with the commercial control. Very promising, compound 2a , ethyl 2‐((6‐fluoro‐5‐(4,5,6,7‐tetrahydro‐1‐oxo‐1H‐isoindol‐2(3H)‐yl)benzo[d]thiazol‐2‐yl)‐sulfanyl)acetate, was recognized as the most potent candidate with K_i value of 0.0091 μm . Further greenhouse screening results demonstrated that some compounds exhibited good herbicidal activity against Chenopodium album at the dosage of 150 g/ha.     

New 1‐Benzyl‐4‐hydroxypiperidine Derivatives as Non‐imidazole Histamine H3 Receptor Antagonists

A series of 1‐benzyl‐4‐(3‐aminopropyloxy)piperidine and 1‐benzyl‐4‐(5‐aminopentyloxy)piperidine derivatives has been prepared. The 1‐benzyl‐4‐hydroxypiperidine derivatives obtained were evaluated for their affinities at recombinant human histamine H₃ receptor, stably expressed in HEK 293T cells. All compounds investigated show moderate to pronounced in‐vitro affinities. The most potent antagonists in this series 9b2 (hH₃R, pK_i = 7.09), 9b1 (hH₃R, pK_i = 6.78), 9b5 (hH₃R, pK_i = 6.99), and 9b6 (hH₃R, pK_i = 6.97) were also tested in vitro as H₃ receptor antagonists – the electrically evoked contraction of the guinea‐pig jejunum. The histaminergic H₁ antagonism of selected compounds 9b1 , 9b2 , and 9b4 – 9b6 was established on the isolated guinea‐pig ileum by conventional methods; the pA₂ values were compared with the potency of pyrilamine. The compounds did not show any H₁ antagonistic activity (pA₂ < 4; for pyrilamine pA₂ = 9.53).