Synthesis and antimicrobial study of novel 1-aryl-2-oxo-indano[3,2-d]pyrido/pyrimido[1,2-b]pyrimidines

A series of 2-(arylidene)-indan-1, 3-diones 1 were prepared by Knoevenagel reaction between indane-1,3-dione and the appropriate araldehydes. The alpha,beta-enones 1 have been used as a component of Michael addition with equimolar amounts of 2-aminopyridine/2-aminopyrimidine to give novel heterocyclic systems 4 and 5, respectively. They are reported here for the first time. The structures of the newly synthesized compounds were confirmed by IR, (1)H-NMR, (13)C-NMR, and elemental analysis. All compounds were screened for their antibacterial and antifungal activities. Some of them showed promising activities.     

Access to 18F‐labelled isoxazoles by ruthenium‐promoted 1,3‐dipolar cycloaddition of 4‐[18F]fluoro‐N‐hydroxybenzimidoyl chloride with alkynes

4‐[¹⁸F]Fluoro‐N‐hydroxybenzimidoyl chloride (¹⁸FBIC), an ¹⁸F‐labelled aromatic nitrile oxide, was developed as building block for Ru‐promoted 1,3‐dipolar cycloaddition with alkynes. ¹⁸FBIC is obtained in a one‐pot synthesis in up to 84% radiochemical yield (RCY) starting from [¹⁸F]fluoride with 4‐[¹⁸F]fluorobenzaldehyde (¹⁸FBA) and 4‐[¹⁸F]fluorobenzaldehyde oxime (¹⁸FBAO) as intermediates, by reaction of ¹⁸FBAO with N‐chlorosuccinimide (NCS). ¹⁸FBIC was found to be a suitable and stable synthon to give access to ¹⁸F‐labelled 3,4‐diarylsubstituted isoxazoles by [Cp*RuCl(cod)]‐catalysed 1,3‐dipolar cycloaddition with various alkynes. So the radiosynthesis of a fluorine‐18–labelled COX‐2 inhibitor [¹⁸F] 1b , a close derivative of valdecoxib, was performed with ¹⁸FBIC and 1‐ethynyl‐4‐(methylsulfonyl)benzene, providing [¹⁸F] 1b in up to 40% RCY after purification in 85 minutes. The application of ¹⁸FBIC as a building block in the synthesis of ¹⁸F‐labelled heterocycles will generally extend the portfolio of available PET radiotracers.     

Synthesis, DNA binding and antiviral activity of new uracil, xanthine, and pteridine derivatives

Some new 6-amino-1,3-dimethyl-5-(substituted methylidene)aminouracils were synthesized. Most of them were cyclized with triethyl orthoformate as a one-carbon source to afford 1,3-dime-thyl-6-substituted pteridine derivatives. Certain uracils gave xanthine instead of the expected pteridine derivatives upon using another one-carbon source such as triethyl orthoacetate or triethyl orthobenzoate. The nucleic acid binding assay revealed that some new compounds showed high affinity, chelation, and fragmentation of nucleic acids whether DNA or RNA contrary to acyclovir that has affinity to DNA only. The antiviral activity of these novel compounds showed that compounds 2e and 2f reduced the cytopathogencity of Peste des petits ruminant virus (PPRV) on Vero cell culture by 60 and 50%, respectively.     

Developmental patterns of Galβ1,3(4)GlcNAc α2,3-sialyltransferase (ST3Gal III) expression in the mouse:In situ hybridization using DIG-labeled RNA probes

Sialic acids are key determinants for biological processes, such as cell-cell interaction and differentiation. Sialyltransferases contribute to the diversity in carbohydrate structure through their attachment of sialic acid in various terminal positions on glycolipid and glycoprotein (N-linked and O-linked) carbohydrate groups. Galbeta 1,3(4)GlcNAc alpha2,3-sialyltransferase (ST3Gal III) is involved in the biosynthesis of sLe(x)and sLe(a) known as selectin ligands and tumor-associated carbohydrate structures. The appearance and differential distribution of ST3Gal III mRNA during mice embryogenesis [embryonic (E) days; E9, E11, E13, E15] were investigated by in situ hybridization with digoxigenin-labeled RNA probes coupled with alkaline phosphatase detection. On E9, all tissues were positive for ST3Gal III mRNA expression, whereas ST3Gal III mRNA on E11 was not detected throughout all tissues. On E13, ST3Gal III mRNA was expressed in different manner in various tissues. In this stage, ST3Gal III mRNA was positive only in the liver, pancreas and bladder. On E15, specific signal for ST3Gal III was detected in the liver, lung and forebrain. These results indicate that ST3GAI III is differently expressed at developmental stages of mice embryo, and this may be importantly related with regulation of organogenesis in mice.     

Design, synthesis and evaluation of novel 2-(aminoalkyl)-isoindoline-1,3-dione derivatives as dual-binding site acetylcholinesterase inhibitors

A new series of 2-(diethylaminoalkyl)-isoindoline-1,3-dione derivatives intended as dual binding site cholinesterase inhibitors were designed using molecular modeling and evaluated as inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and the formation of the β-amyloid (Aβ) plaques. For AChE inhibitory activity, the spectrophotometric method of Ellman and the electrophoretically mediated microanalysis assay were used, giving good results. Most of the synthesized compounds had AChE inhibitory activity with IC(50) values ranging from IC(50) = 0.9 to 19.5 μM and weak Aβ anti-aggregation inhibitory activity. These results support the outcome of docking studies which tested compounds targeting both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. The most promising selective AChE inhibitors are compounds 10 (IC(50) = 1.2 μM) and 11 (IC(50) = 1.1 μM), with 6-7 methylene chains, which also inhibit Aβ fibril formation.     

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.     

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.     

支气管肺泡灌洗液葡聚糖检测对早期诊断侵袭性肺真菌感染的价值

目的：探讨支气管肺泡灌洗液（BALF）中的（1,3）-β-D葡聚糖（BG）检测对早期诊断侵袭性肺真菌感染（IPFI）的价值。方法（1）选择2011年6月至2013年12月六安市人民医院收治的172例患者,其中确诊IPFI组、普通感染组和无肺部感染组各32例,共96例,此外入院时有真菌感染的高危因素但早期未确诊IPFI者76例作进一步研究,每日连续真菌检测直至明确是否为IPFI,进而分诊断组、排除组。全部对象均予支气管肺泡灌洗,留取BALF及血浆进行G试验（ BG抗原检测）,对数据采用独立样本秩和检验来检验并绘制受试者工作ROC曲线,确定两种标本检测方法诊断IPFI的最佳临界值。结果（1） BALF G试验水平：IPFI组明显高于单纯肺炎组和非感染组。（2）76例未确诊病例在随后的5 d检查中7例确诊IPFI,22例临床诊断,29例剔除,18例排除真菌感染。（3）诊断组BALF、血浆BG水平均显著高于排除组,BALF BG浓度为149．5 ng· L－1时对应的约登指数值最大,为0．87,血浆BG浓度为81 ng· L－1时对应的约登指数值最大,为0．81。（4）诊断组BALF BG峰值浓度出现时间早于血浆,同时诊断的特异性高于血浆。结论（1） BALF中BG的含量较血浆中升高更明显,且BALF G试验在区分单纯肺炎和IPFI方面更具有参考价值。（2） BALF G试验特异度、敏感度均明显高于血浆G试验,且峰值出现早于血浆,具有更早、更准确、更高的临床诊断价值。（3）BALF G试验的最佳诊断临界值是149．5 ng· L－1,其诊断IPFI的特异性和敏感性均较高。     

Synthesis,radiosynthesis and in vivo evaluation of [123I]‐4‐(2‐(bis(4‐fluorophenyl)methoxy)ethyl)‐1‐(4‐iodobenzyl)piperidine as a selective tracer for imaging the dopamine transporter

Dopamine transporter (DAT) neuroimaging is a useful tool in Parkinson's disease diagnosis, staging and follow‐up providing information on the integrity of the dopaminergic neurotransmitter system in vivo. 4‐(2‐(Bis(4‐fluorophenyl)methoxy)ethyl)‐1‐(4‐iodobenzyl)piperidine (7) has nanomolar affinity for DAT and better selectivity over the other monoamine transporters compared with the existing SPECT radioligands for DAT. The aim of this study was to synthesize and evaluate [¹²³I]‐7 as an in vivo tracer for DAT. The tributylstannyl precursor was synthesized with an overall yield of 25%. [¹²³I]‐7 was synthesized by electrophilic destannylation with a yield of 40±10%. Radiochemical purity appeared to be >98%, whereas specific activity was at least 667 GBq/µmol. Biodistribution studies in mice showed brain uptake of 0.96±0.53%ID/g at 30 s post injection (p.i.) and 0.26±0.02%ID/g at 3 h p.i. High blood activity was observed at all time points. Pretreatment with Cyclosporin A raised brain uptake indicating that [¹²³I]‐7 is transported by P‐glycoprotein (P‐gp) pumps. In rats, regional brain distribution of [¹²³I]‐7 was not in agreement with DAT distribution. These results indicate that [¹²³I]‐7 is not suitable for mapping DAT in vivo but could be a useful tracer for the P‐gp transporter. Copyright © 2009 John Wiley & Sons, Ltd.     

Synthesis and effects on intracellular calcium of some 1,3-bis-(heteroaryl substituted)benzene derivatives

A series of 1,3-bis-(heteroaryl substituted)benzene derivatives was designed as promising molecules which might increase intracellular Ca2+ level in F2408 fibroblast-like cells by affecting the Ca2+ channels on plasma membrane. Mentioned compounds were obtained by the treatment of isophtalaldehyde with benzil or 1,2-phenylenediamine derivatives. In this way, 13 compounds were synthesised and their structure elucidations were performed by IR, 1H NMR and mass spectroscopic data and elemental analysis results. Some of the compounds showed Ca2+ being released from the intact cells.     

Synthesis of deuterated herbicidal ZJ0273, ZJ0702, ZJ0777, and SIOC0163

ZJ0273 (propyl 4‐(2‐(4,6‐dimethoxypyrimidin‐2‐yloxy)benzylamino)benzoate), ZJ0702 (isopropyl 4‐(2‐(4,6‐dimethoxypyrimidin‐2‐yloxy)benzylamino)benzoate), ZJ0777 (2‐bromo‐N‐(2‐(4,6‐dimethoxypyrimidin‐2‐yloxy)benzyl)aniline), and SIOC0163 (5‐bromo‐N‐(2‐(4,6‐dimethoxypyrimidin‐2‐yloxy)benzyl)pyridin‐2‐amine) are active ingredients in oilseed rape herbicides. The middle aromatic ring‐deuterated form of ZJ0273 was synthesized from (²H₆)phenol and have been successfully used as tracer in its metabolism and degradation study. The methoxyl‐deuterated forms of four ingredients were synthesized from (²H₄)methanol, respectively, and they could be used as internal standards in quantitation of herbicide residue in rapeseed and its downstream foodstuff by using HPLC‐MS/MS. Copyright © 2010 John Wiley & Sons, Ltd.     

Mechanism of action of 2-haloethylnitrosoureas on deoxyribonucleic acid. Nature of the intermediates from nitrosourea decomposition.

Direct current (DC) and differential pulse polarographic analyses were used to measure the rates of decomposition of a series of 2-haloethylnitrosoureas in aqueous solution. Measured by these methods, the rates of the first and rate-determining step which show a marked pH and solvent dependence agree with the overall rate of decomposition measured by gas evolution. In the 1,3-bis(haloethyl)-1-nitrosourea series, changing the nature of the halogen X has a small effect on the rate of decomposition. In the 3-cyclohexyl-1-(2-haloethyl)-1-nitrosourea series, changing X for OH or OCH₃ results in the rate of hydrolysis being reduced considerably. A free—NH₂ group in the nitrosourea structure as in CNU, MNU, ENU, CPNU, 4-CBNU and 5-CPNU accelerates considerably the rate of decomposition relative to the BCNU and CCNU series. Arrhenius parameters for the decomposition in aqueous pH 7.1 solution in the temperature range 28–47° were obtained for BFNU, BCNU and BBNU: log A, ?20.1± 1.4,?21.6± 0.7 and ?22.3±1.6; E_a, 24.4 ± 2.0, 26.5± 1.0 and 27.2 m 2.3 kcal/mole. The corresponding values for BINU were estimated as log A,?23.3± 3.0; E_a, 28.0± 3.0 kcal/mole. Examination of the decomposition products of 1,3-bis(2-chloropropyl)-1-nitrosourea (BCNU-β-Me) and 1,3-bisl 1-(chloromethyl)ethyl]-1-nitrosourea (BCNU-α-Me) favors decomposition pathway B via the diazohydroxide and cyclic chloronium ion for BCNU-β-Me and via the diazohydroxide and/or 2-chloro-1-methylethyl carbonium ion for BCNU-α-Me. While there is no evidence for the contribution of pathway A via a 2-imino-N-nitrosooxazolidinone for these compounds, consideration of product type and yields implicates a third decomposition pathway, via a 1,2,3-oxadiazoline intermediate. Additional evidence for an oxadiazoline intermediate is obtained by the isolation of 2-bromoethanol when BCNU is decomposed in the presence of a high concentration of sodium bromide.     

血浆（1，3）-β-D葡聚糖检测对侵袭性真菌病的诊断意义

目的：探讨血浆（1,3）-β-D葡聚糖检测对侵袭性真菌病的早期诊断意义。方法通过回顾性分析105例怀疑侵袭性真菌病的住院患者的血浆（1,3）-β-D葡聚糖含量和真菌培养结果,分别计算两种方法的阳性率及灵敏度、特异度、阳性和阴性预测值。结果侵袭性真菌病患者的血浆（1,3）-β-D葡聚糖检测阳性率和真菌培养阳性率分别是为80．00％和66．67％,两组差异有统计学意义（P＜0．05）;血浆（1,3）-β-D葡聚糖检测阳性者血浆（1,3）-β-D葡聚糖含量为（62．0±21．34）ng·L－1,阴性者为（5．1±2．03）ng·L－1,两组差异有统计学意义（P＜0．05）;葡聚糖检测灵敏度和特异度为80．0％和91．7％,葡聚糖检测的阳性预测值和阴性预测值分别为87．8％和85．9％,均较真菌培养高。结论血浆（1,3）-β-D葡聚糖检测方法快速、阳性率高、灵敏度和特异度高,可用于侵袭性真菌病的早期诊断。     

Synthesis of carbon‐14 labeled ZJ0712, a novel strobilurin fungicide

ZJ0712, a broad‐spectrum fungicidal ingredient of strobilurin, exhibits a high protective and curative activity against plant pathogenic fungi. To support the study on its metabolism, residue, environmental behavior, and fate for safety evaluation, two versions of carbon‐14 labeled ZJ0712, methyl (E)‐2‐(2‐((2,5‐dimethylphenoxy)methyl)phenyl)‐3‐methoxy[2‐¹⁴C]acrylate ( 2 ) and methyl (E)‐2‐(2‐((2,5‐dimethyl[phenyl‐U‐¹⁴C₆]phenoxy)methyl)phenyl)‐3‐methoxyacrylate ( 3 ), were synthesized from barium [¹⁴C]carbonate in 6‐step yield of 47% and from 2,5‐dimethyl[phenyl‐U‐¹⁴C₆]phenol in the yield of 91%, respectively.     

Two new polyacetylenic compounds from Atractylodes chinensis (DC.) Koidz.

Two new polyacetylenic compounds, (6E,12Z)-tetradecadiene-8,10-diyne-1,3-diol (1) and (6Z,12Z)-tetradecadiene-8,10-diyne-1,3-diol (2), were isolated from Atractylodes chinensis (DC.) Koidz. Their structures were established by analysis of spectroscopic data.     

Antileishmanial and antibacterial activity of a new pyrazole derivative designated 4-[2-(1-(ethylamino)-2-methyl- propyl)phenyl]-3-(4-methyphenyl)-1-phenylpyrazole

Here, we report for the first time the synthesis and the antileishmanial activity of a new pyrazole derivative, namely 4-[2-(1-(ethylamino)-2-methylpropyl)phenyl]-3-(4-methyphenyl)-1-phenylpyrazole). Micromolar concentrations of this compound were found to inhibit the in vitro multiplication of Leishmania tropica, Leishmania major, and Leishmania infantum, three species causing different forms of leishmaniasis. Furthermore, the 50% inhibitory concentration (IC50) values for the compound are only slightly higher than those of amphotericin B, one of the most active antileishmanial agents used as a satisfactory substitute in cases not responding to pentostam. The IC50 values after 48 h for L. tropica, L. major, and L. infantum promastigote growth were 0.48 microg/mL, 0.63 microg/mL and 0.40 microg/mL, respectively for the compound, while they were 0.23 microg/mL, 0.29 microg/mL and 0.24 microg/mL, respectively for amphotericin B. We also tested this compound for its antibacterial activity against several bacteria. The strongest antibacterial activity was observed against Entrococcus feacalis and Staphylococcus aureus with a minimal inhibitory concentration (MIC) of 60 microg/mL.     

Synthesis and antinociceptive activity of (5-chloro-2(3H)-benzothiazolon-3-yl)propanamide derivatives

Ten new (5-chloro-2(3H)-benzothiazolon-3-yl)propanamide derivatives have been synthesized. The compounds were tested for antinociceptive activity by tail clip, tail flick, hot plate and writhing test by using aspirin and dipyrone as standards. Among these compounds, 1-[3-(5-chloro-2(3H)-benzothiazolon-3-yl)-propanoyl]-4-(4-chlorophenyl)piperazine (11e) has been found to be significantly more active than the other compounds synthesized as well as the standards in all tests.     

Synthesis of tritium labelled 3(R)‐HETE and 3(R),18(R/S)‐DiHETE through a common synthetic route

An efficient procedure for the synthesis of 3‐hydroxyoxylipins labelled with tritium on all double bond positions is reported. The synthetic scheme involves a joint route for the formation of tetraacetylenic precursors followed by stereoselective reduction of the triple bonds either with hydrogen or tritium. The final tritiated products were obtained with specific activities ranging from 1.65 to 1.80 Ci/mmol. Copyright © 2003 John Wiley & Sons, Ltd.     

Synthesis and pharmacological activity of 2-(substituted)-3-{2-[(4-phenyl-4-cyano)piperidino]ethyl}-1,3-thiazolidin-4-ones

Loperamide is a well-known peripherally acting opiate used for the treatment of diarrhoea. To gain more knowledge on the structure-activity relationships of antidiarrhoeal drugs and to develop new active molecules, a series of aryl-cyano-piperidinoalkyl-thiazolidinones related to Loperamide was synthesized and screened for antidiarrhoeal activity in mice by castor oil test. To characterize the potency and toxicity of the synthesized compounds ED50 and LD50 values were also determined. The thiazolidinones 2-6 displayed antidiarrhoeal activity at doses ranging between 15 and 82 mg/kg. Although the results show that the synthesized compounds are 15- to 80-fold less active respect to the reference compound, Loperamide, they are much less toxic (> or = 1000 mg/kg and 108.9 mg/kg, respectively). Besides, to evaluate the involvement of opioid receptors in antidiarrhoeal activity, Naloxone was administered prior to test the 2-phenyl-3-{2-[(4-phenyl-4-cyano)piperidino]ethyl}-1,3-thiazolidin-4-one (2), the more active compound of this series. The results obtained by this study, suggest that the antidiarrhoeal activity of this series of thiazolidinone derivatives could involve the opioid receptors.