Angiotensin‐(1–7) treatment ameliorates angiotensin II‐induced apoptosis of human umbilical vein endothelial cells

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Effect of pravastatin on bleomycin‐induced acute lung injury and pulmonary fibrosis

1. Pravastatin is best known for its antilipidemic action. Recent studies have shown that statins have immunomodulatory and anti‐inflammatory effects. The present study aimed to determine whether or not pravastatin can attenuate acute lung injury and fibrosis in a mouse model. 2. Bleomycin was given to C57BL6 mice through intratracheal instillation. Pravastatin was given through intraperitoneal injection. To study the effect of pravastatin on the early inflammatory phase and the late fibrotic phase, mice were killed on days 3, 7, 14 and 21. 3. Pravastatin attenuated the histopathological change of bleomycin‐induced lung injury and fibrosis. The accumulation of neutrophils and increased production of tumor necrosis factor‐α in bronchoalveolar lavage fluid were inhibited in the early inflammatory phase. Pravastatin effectively inhibited the increase of lung hydroxyproline content induced by bleomycin. Furthermore, pravastatin reduced the increased expression of transforming growth factor (TGF)‐β1, connective tissue growth factor (CTGF), RhoA and cyclin D1. The increased levels of TGF‐β1 and CTGF mRNA expression were also significantly inhibited by pravastatin. 4. Pravastatin effectively attenuated bleomycin‐induced lung injury and pulmonary fibrosis in mice. Our results provide evidence for the therapeutic potential of pravastatin in the treatment of acute lung injury and pulmonary fibrosis.     

Role of α1D‐adrenoceptors in vascular wall hypertrophy during angiotensin II‐induced hypertension

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Poly(ADP‐ribose)polymerase 1 inhibition protects against age‐dependent endothelial dysfunction

Age‐related endothelial dysfunction is closely associated with the local production of reactive oxygen species (ROS) within and in the vicinity of the vascular endothelium. Oxidant‐induced DNA damage can activate the nuclear enzyme poly(ADP‐ribose) polymerase 1 (PARP‐1), leading to endothelial dysfunction in various pathophysiological conditions. The present study aimed to investigate the role of PARP‐1 in age‐dependent changes in endothelial cell function and its underlying mechanism. Wild‐type (WT) and PARP‐1^?/? mice were divided into young (2 months) and old (12 months) groups. Isolated aortic rings were suspended to record isometric tension to assess endothelial function. Nitric oxide (NO) production and content in plasma were detected by spectrophotometry. Superoxide ( production was detected by dihydroethidium. Expression of PARP‐1, endothelial nitric oxide synthase (eNOS), induced nitric oxide synthase (iNOS), and arginase‐2 (Arg2) was assessed by western blot analysis. Endothelium‐dependent relaxation in response to acetylcholine was lost in old WT, but not PARP‐1^?/?, mice. Endothelium‐independent vasodilation was not impaired in aging mice. Production of was greater in aging WT mice than young or aging PARP‐1^?/? mice. eNOS expression was not affected by aging in WT or PARP‐1^?/? mice, but p‐eNOS expression decreased and iNOS and Arg2 levels were upregulated only in aging WT mice. In conclusion, PARP‐1 inhibition may protect against age‐dependent endothelial dysfunction, potentially by regulating NO bioavailability via iNOS. Inhibition of PARP‐1 may help in vascular aging prevention.     

Inhibition of macrophage‐derived foam cell formation by ezetimibe via the caveolin‐1/MAPK pathway

Ezetimibe, a selective inhibitor of intestinal cholesterol absorption, effectively reduces plasma cholesterol, but its effect on atherosclerosis is unclear. Foam cell formation has been implicated as a key mediator during the development of atherosclerosis. The purpose of this study was to investigate the effects of ezetimibe on foam cell formation and explore the underlying mechanism. The results presented here show that ezetimibe reduces atherosclerotic lesions in apolipoprotein E deficient (apoE‐/‐) mice by lowering cholesterol levels. Treatment of macrophages with Chol:MβCD resulted in foam cell formation, which was concentration‐dependently inhibited by the presence of ezetimibe. Mechanically, ezetimibe treatment downregulated the expression of CD36 and scavenger receptor class B1 (SR‐B1), but upregulated the expression of apoE and caveolin‐1 in macrophage‐derived foam cells, which kept consistent with our microarray results. Moreover, treatment with ezetimibe abrogated the increase of phospho‐extracellular signal regulated kinase (ERK) 1/2 and their nuclear accumulation in foam cells. Inhibition of the MAPK pathway by the MEK inhibitor PD98059 attenuated the inhibitory effect of ezetimibe on the expression of p‐ERK1/2 and caveolin‐1. Taken together, these results showed that ezetimibe suppressed foam cell formation via the caveolin‐1/MAPK signalling pathway, suggesting that inhibition of foam cell formation might be a novel mechanism underlying the anti‐atherosclerotic effect of ezetimibe.     

Age‐dependent electrocardiographic changes in Pgc‐1β deficient murine hearts

Increasing evidence implicates chronic energetic dysfunction in human cardiac arrhythmias. Mitochondrial impairment through Pgc‐1β knockout is known to produce a murine arrhythmic phenotype. However, the cumulative effect of this with advancing age and its electrocardiographic basis have not been previously studied. Young (12‐16 weeks) and aged (>52 weeks), wild type (WT) (n = 5 and 8) and Pgc‐1β^?/? (n = 9 and 6), mice were anaesthetised and used for electrocardiographic (ECG) recordings. Time intervals separating successive ECG deflections were analysed for differences between groups before and after β1‐adrenergic (intraperitoneal dobutamine 3 mg/kg) challenge. Heart rates before dobutamine challenge were indistinguishable between groups. The Pgc‐1β^?/? genotype however displayed compromised nodal function in response to adrenergic challenge. This manifested as an impaired heart rate response suggesting a functional defect at the level of the sino‐atrial node, and a negative dromotropic response suggesting an atrioventricular conduction defect. Incidences of the latter were most pronounced in the aged Pgc‐1β^?/? mice. Moreover, Pgc‐1β^?/? mice displayed electrocardiographic features consistent with the existence of a pro‐arrhythmic substrate. Firstly, ventricular activation was prolonged in these mice consistent with slowed action potential conduction and is reported here for the first time. Additionally, Pgc‐1β^?/? mice had shorter repolarisation intervals. These were likely attributable to altered K⁺ conductance properties, ultimately resulting in a shortened QT_c interval, which is also known to be associated with increased arrhythmic risk. ECG analysis thus yielded electrophysiological findings bearing on potential arrhythmogenicity in intact Pgc‐1β^?/? systems in widespread cardiac regions.     

Investigation of anti‐inflammatory,nitric oxide donating,vasorelaxation and ulcerogenic activities of 1, 3‐diphenylprop‐2‐en‐1‐one derivatives in animal models

The main aim of this work is to find out novel chemical moieties with potent anti‐inflammatory and vasorelaxant activities with reduced gastric toxicities. For fulfilling the above aim, here we investigated novel chalcones (1, 3‐diphenylprop‐2‐en‐1‐one derivatives) with nitric oxide (NO) and hydrogen sulphide (H₂S) donating potency for anti‐inflammatory activity by carrageenan‐induced rat paw oedema. These molecules then further evaluated for in‐vitro NO‐releasing potency and vasorelaxation effect on isolated adult goat aortic tissue. The promising molecules were further screened for ulcerogenic activity in the rat model. The tested compounds produced % inhibition in paw oedema ranging from 29.16% to 79.69% and standard drug Diclofenac sodium produced 85.30% reduction in paw oedema after 5 hours. Out of this dataset, compounds AI1, AI7, Ca1, B2, B10, D2, and E8 showed 73.01%, 79.69%, 75.02%, 75.46%, 74.35%, 73.9% and 74.35% reduction in paw oedema respectively, which is approximately 80%–90% to that of standard Diclofenac sodium. The compound Ca1 was found to release 0.870 ± 0.025 mol/mol of NO and standard Glyceryl trinitrate (GTN) was found to release 0.983 ± 0.063 mol/mol of NO. The compound Ca1 produced 950.2 μmol/L of EC₅₀ whereas standard GTN produced 975.8 μmol/L of EC₅₀ for aortic smooth relaxation. The compounds Ca1 produced 0.1117 of ulcer index which is far less than that of standard Diclofenac sodium (1.148). The potent lead molecules were further evaluated to understand the mechanism of vasorelaxation by using specific antagonists or blockers of NO and H₂S.     

Role of tumour necrosis factor‐a in the regulation of T‐type calcium channel current in HL‐1 cells

Increasing evidence indicates that inflammation contributes to the initiation and perpetuation of atrial fibrillation (AF). Although tumour necrosis factor (TNF)‐α levels are increased in patients with AF, the role of TNF‐α in the pathogenesis of AF remains unclear. Besides L‐type Ca²⁺ currents (I_Ca,L), T‐type Ca²⁺ currents (I_Ca,T) also plays an important role in the pathogenesis of AF. This study was designed to use the whole‐cell voltage‐clamp technique and biochemical assays to explore if TNF‐α is involved in the pathogenesis of AF through regulating I_Ca,T in atrial myocytes. It was found that compared with sinus rhythm (SR) controls, T‐type calcium channel (TCC) subunit mRNA levels were decreased, while TNF‐α expression levels were increased, in human atrial tissue from patients with AF. In murine atrial myocyte HL‐1 cells, after culturing for 24 h, 12.5, 25 and 50 ng/mL TNF‐α significantly reduced the protein expression levels of the TCC α1G subunit in a concentration‐dependent manner. The peak current was reduced by the application of 12.5 or 25 ng/mL TNF‐α in a concentration‐dependent manner (from ?15.08 ± 1.11 pA/pF in controls to ?11.89 ± 0.83 pA/pF and ?8.54 ± 1.55 pA/pF in 12.5 or 25 ng/mL TNF‐α group respectively). TNF‐α application also inhibited voltage‐dependent inactivation of I_Ca,T, shifted the inactivation curve to the left. These results suggest that TNF‐α is involved in the pathogenesis of AF, probably via decreasing I_Ca,T current density in atrium‐derived myocytes through impaired channel function and down‐regulation of channel protein expression. This pathway thus represents a potential pathogenic mechanism in AF.     

Adventitia removal does not modify the α1D‐adrenoceptors response in aorta during hypertension and ageing

1 The aim of the current study was to characterize the α₁‐adrenergic receptors (α₁‐ARs) present in the isolated tunica media of aorta, in normotensive Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats during the course of ageing and hypertension (rats of 1, 3, 6 and 12 months of age). In all vessels, endothelium was removed. 2 In isolated aortic rings, phenylephrine increased contraction in a concentration‐ and age‐dependent manner and was impaired in old SHR compared with WKY rats. 3 The α₁‐AR selective antagonist prazosin showed high affinity (pA₂) in vessels from both rat strains. 4 The potency of the α_1A‐AR selective antagonists, RS 100329 (5‐methyl‐3‐[3‐[4‐[2‐(2,2,2,‐trifluoroethoxy) phenyl]‐1‐piperazinyl] propyl]‐2,4‐(1H)‐pyrimidinedione) and 5‐methylurapidil in antagonizing aortic phenylephrine‐responses was low. 5 The α_1D‐AR selective antagonist, BMY 7378 (8‐[2‐[4‐(2‐methoxyphenyl)‐1 piperazynil] ethyl]‐8‐azaspiro [4.5] decane‐7,9‐dione) potently blocked phenylephrine‐induced responses in aorta from both strains and at all ages. 6 Adventitia removal decreased E_max in older rats and modified the relative affinity (pD₂), but did not affect the affinity of the selective antagonists. 7 The results suggest that aorta tunica α_1D‐AR is the main subtype involved in phenylephrine‐induced contraction of rat aorta, while α_1A‐AR plays only a minor role. 8 Ageing and hypertension did not modify α₁‐ARs in the blood vessel and the tunica adventitia does not seem to participate in contraction, even though α₁‐ARs are expressed.     

Attenuation of the LPS‐induced,ERK‐mediated upregulation of fibrosis‐related factors FGF‐2, uPA,MMP‐2, and MMP‐9 by Carthamus tinctorius L in cardiomyoblasts

Severe and potentially fatal hypotension and cardiac contractile dysfunction are common symptoms in patients with sepsis. LPS was previously found to dramatically upregulate expression of fibrosis‐related factors FGF‐2, uPA, MMP‐2, and MMP‐9 in primary cardiac fibroblasts. MMPs are capable of denaturing and degrading fibrillar collagens and other components of the extracellular matrix (ECM). Studies have shown that dysregulation of expression of MMPs is associated with development of myocardial extracellular matrix remodeling and cardiac fibrosis, which contribute to progression of heart failure. In this study, H9c2 cells and cardiac fibroblasts were divided into five treatment groups: control, LPS (1 μg/mL) and three concentrations of FC_EtOH (Carthami Flos ethanolic extract) (31.25, 62.5, and 125 μg/mL). Phosphorylation of ERK‐1/2 was observed to be rapidly induced upon treatment with LPS. In contrast, it was significantly suppressed by the administration of FC_EtOH (125 μg/mL). Effects of FC_EtOH on LPS‐induced MMP‐2 and MMP‐9 expression in H9c2 cells occurred directly through ERK1/2 were determined. H9c2 cells were therefore pretreated with EGF‐R to activate ERK pathway. Both protein levels of MMP‐2 and MMP‐9 and immunefluorescent signals of MMP‐9 were significantly enhanced by EGFR. In contrast, MMP‐2 and MMP‐9 were significantly reduced after FC_EtOH administration. Based on these findings, the authors concluded that FC_EtOH elicits a protective effect against LPS‐induced cardio‐fibrosis through the ERK1/2 pathway. Carthamus tinctorius L may potentially serve as a cardio‐protective agent against LPS‐ induced cardiac fibrosis. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 754–763, 2017.     

Potencies of vitamin D analogs, 1α‐hydroxyvitamin D3, 1α‐hydroxyvitamin D2 and 25‐hydroxyvitamin D3, in lowering cholesterol in hypercholesterolemic mice in vivo

Vitamin D₃ and the synthetic vitamin D analogs, 1α‐hydroxyvitamin D₃ [1α(OH)D₃], 1α‐hydroxyvitamin D₂ [1α(OH)D₂] and 25‐hydroxyvitamin D₃ [25(OH)D₃] were appraised for their vitamin D receptor (VDR) associated‐potencies as cholesterol lowering agents in mice in vivo. These precursors are activated in vivo: 1α(OH)D₃ and 1α(OH)D₂ are transformed by liver CYP2R1 and CYP27A1 to active VDR ligands, 1α,25‐dihydroxyvitamin D₃ [1,25(OH)₂D₃] and 1α,25‐dihydroxyvitamin D₂ [1,25(OH)₂D₂]_, respectively. 1α(OH)D₂ may also be activated by CYP24A1 to 1α,24‐dihydroxyvitamin D₂ [1,24(OH)₂D₂], another active VDR ligand. 25(OH)D₃, the metabolite formed via CYP2R1 and or CYP27A1 in liver from vitamin D₃, is activated by CYP27B1 in the kidney to 1,25(OH)₂D₃. In C57BL/6 mice fed the high fat/high cholesterol Western diet for 3 weeks, vitamin D analogs were administered every other day intraperitoneally during the last week of the diet. The rank order for cholesterol lowering, achieved via mouse liver small heterodimer partner (Shp) inhibition and increased cholesterol 7α‐hydroxylase (Cyp7a1) expression, was: 1.75 nmol/kg 1α(OH)D₃ > 1248 nmol/kg 25(OH)D₃ (dose ratio of 0.0014) > > 1625 nmol/kg vitamin D₃. Except for 1.21 nmol/kg 1α(OH)D₂ that failed to lower liver and plasma cholesterol contents, a significant negative correlation was observed between the liver concentration of 1,25(OH)₂D₃ formed from the precursors and liver cholesterol levels. The composite results show that vitamin D analogs 1α(OH)D₃ and 25(OH)D₃ exhibit cholesterol lowering properties upon activation to 1,25(OH)₂D₃: 1α(OH)D₃ is rapidly activated by liver enzymes and 25(OH)D₃ is slowly activated by renal Cyp27b1 in mouse.     

Exercise training protects against atherosclerotic risk factors through vascular NADPH oxidase,extracellular signal‐regulated kinase 1/2 and stress‐activated protein kinase/c‐Jun N‐terminal kinase downregulation in obese rats

Exercise training reverses atherosclerotic risk factors associated with metabolic syndrome and obesity. The aim of the present study was to determine the molecular anti‐inflammatory, anti‐oxidative and anti‐atherogenic effects in aorta from rats with high‐fat diet‐induced obesity. Male Sprague‐Dawley rats were placed on a high‐fat (HFD) or control (CD) diet for 12 weeks. The HFD rats were then divided into four groups: (i) sedentary HFD‐fed rats (HFD‐S); (ii) exercise trained (motor treadmill 5 days/week, 60 min/day, 12 weeks) HFD‐fed rats (HFD‐Ex); (iii) modified diet (HFD to CD) sedentary rats (HF/CD‐S); and (iv) an exercise‐trained modified diet group (HF/CD‐Ex). Tissue levels of NADPH oxidase (activity and expression), NADPH oxidase (Nox) 1, Nox2, Nox4, p47^phox, superoxide dismutase (SOD)‐1, angiotensin AT₁ and AT₂ receptors, phosphorylated mitogen‐activated protein kinase (MAPK; extracellular signal‐regulated kinase (ERK) 1/2, stress‐activated protein kinase (SAPK)/c‐Jun N‐terminal kinase (JNK)) and vascular cell adhesion molecule‐1 (VCAM‐1) were determined in the aorta. Plasma cytokines (tumour necrosis factor (TNF)‐α and interleukin (IL)‐6) levels were also measured. Obesity was accompanied by increases in NADPH oxidase activity, p47^phox translocation, Nox4 and VCAM‐1 protein expression, MAPK (ERK1/2, SAPK/JNK) phosphorylation and plasma TNF‐α and IL‐6 levels. Exercise training and switching from the HFD to CD reversed almost all these molecular changes. In addition, training increased aortic SOD‐1 protein expression and decreased ERK1/2 phosphorylation. These findings suggest that protective effects of exercise training on atherosclerotic risk factors induced by obesity are associated with downregulation of NADPH oxidase, ERK1/2 and SAPK/JNK activity and increased SOD‐1 expression.     

Role of cyclooxygenase‐1 and ‐2 in endothelium‐dependent contraction of atherosclerotic mouse abdominal aortas

The objective of this study was to determine the role of cyclooxygenase (COX)‐1 or ‐2 in endothelium‐dependent contraction under atherosclerotic conditions. Atherosclerosis was induced in apoE knockout (apoE^?/?) mice and those with COX‐1^?/? (apoE^?/?‐COX‐1^?/?) by feeding with high fat and cholesterol food. Aortas (abdominal or the whole section) were isolated for functional and/or biochemical analyses. As in non‐atherosclerotic conditions, the muscarinic receptor agonist acetylcholine (ACh) evoked an endothelium‐dependent, COX‐mediated contraction following NO synthase (NOS) inhibition in abdominal aortic rings from atherosclerotic apoE^?/? mice. Interestingly, COX‐1 inhibition not only abolished such a contraction in rings showing normal appearance, but also diminished that in rings with plaques. Accordingly, only a minor contraction (<30% that of apoE^?/? counterparts) was evoked by ACh (following NOS inhibition) in abdominal aortic rings of atherosclerotic apoE^?/?‐COX‐1^?/? mice with plaques, and none was evoked in those showing normal appearance. Also, the contraction evoked by ACh in apoE^?/?‐COX‐1^?/? abdominal aortic rings with plaques was abolished by non‐selective COX inhibition, thromboxane‐prostanoid (TP) receptor antagonism, or endothelial denudation. Moreover, it was noted that ACh evoked a predominant production of the prostacyclin (PGI₂, which mediates abdominal aortic contraction via TP receptors in mice) metabolite 6‐keto‐PGF_1α, which was again sensitive to COX‐1 inhibition or COX‐1^?/?. Therefore, in atherosclerotic mouse abdominal aortas, COX‐1 can still be the major isoform mediating endothelium‐dependent contraction, which probably results largely from PGI₂ synthesis as in non‐atherosclerotic conditions. In contrast, COX‐2 may have only a minor role in such response limited to areas of plaques under the same pathological condition.     

Comparative effects of 1α‐hydroxyvitamin D3 and 1,25‐dihydroxyvitamin D3 on transporters and enzymes in fxr(+/+) and fxr(‐/‐) mice

Previous studies have shown that 1α,25‐dihydroxyvitamin D₃ [1,25(OH)₂D₃] treatment in mice resulted in induction of intestinal and renal Cyp24a1 and Trpv6 expression, increased hepatic Cyp7a1 expression and activity, as well as higher renal Mdr1/P‐gp expression. The present study compared the equimolar efficacies of 1α‐hydroxyvitamin D₃ [1α(OH)D₃] (6 nmol/kg i.p. q2d × 4), a lipophilic precursor with a longer plasma half‐life that is converted to 1,25(OH)₂D₃, and 1,25(OH)₂D₃ on vitamin D receptor (VDR) target genes. To clarify whether changes in VDR genes was due to VDR and not secondary, farnesoid X receptor (FXR)‐directed effects, namely, lower Cyp7a1 expression in rat liver due to increased bile acid absorption, wildtype [fxr(+/+)] and FXR knockout [fxr(‐/‐)] mice were used to distinguish between VDR and FXR effects. With the exception that hepatic Sult2a1 mRNA was increased equally well by 1α(OH)D₃ and 1,25(OH)₂D₃, 1α(OH)D₃ treatment led to higher increases in hepatic Cyp7a1, renal Cyp24a1, VDR, Mdr1 and Mrp4, and intestinal Cyp24a1 and Trpv6 mRNA expression in both fxr(+/+) and fxr(‐/‐) mice compared to 1,25(OH)₂D₃ treatment. A similar induction in protein expression and microsomal activity of hepatic Cyp7a1 and renal P‐gp and Mrp4 protein expression was noted for both compounds. A higher intestinal induction of Trpv6 was observed, resulting in greater hypercalcemic effect following 1α(OH)D₃ treatment. The higher activity of 1α(OH)D₃ was explained by its rapid conversion to 1,25(OH)₂D₃ in tissue sites, furnishing higher plasma and tissue 1,25(OH)₂D₃ levels compared to following 1,25(OH)₂D₃‐treatment. In conclusion, 1α(OH)D₃ exerts a greater effect on VDR gene induction than equimolar doses of 1,25(OH)₂D₃ in mice. Copyright © 2013 John Wiley & Sons, Ltd.     

Hypolipidaemic activity of orally administered diphenyl diselenide in Triton WR‐1339‐induced hyperlipidaemia in mice

Objectives A significant association between the trace element selenium and hyper‐cholesterolaemia has been reported. This study was designed to investigate a potential hypolipidaemic effect of diphenyl diselenide ((PhSe)₂) in Triton WR‐1339‐induced hyperlipidaemia in mice. Methods Triton was administered intraperitoneally (400 mg/kg) to overnight‐fasted mice to develop acute hyperlipidaemia. (PhSe)₂ was administered orally (10 mg/kg) 30 min before Triton. At 24 h after Triton injection, blood samples were collected to measure plasma lipid levels. The hepatic thiobarbituric acid reactive substances and ascorbic acid levels as well as catalase and glutathione peroxidase activity were recorded. Key findings (PhSe)₂ administration significantly lowered total cholesterol, non‐high‐density lipoprotein‐cholesterol and triglycerides, whilst it increased high‐density lipoprotein‐cholesterol levels in plasma of hyperlipidaemic mice. Neither oxidative stress nor the antioxidant effect of (PhSe)₂ was observed in the mouse liver in this experimental protocol. Conclusions These findings indicated that (PhSe)₂ was able to lower plasma lipid concentrations. Further studies are needed to elucidate the exact mechanism by which (PhSe)₂ exerted its hypolipidaemic effect in the management of hyperlipidaemia and atherosclerosis.     

2,3,4',5-Tetrahydroxystilbene-2-O-β-d-glucoside inhibits angiotensin II-induced cardiac fibroblast proliferation via suppression of the reactive oxygen species-extracellular signal-regulated kinase 1/2 pathway

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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.