新型苯并咪唑类化合物的合成及抗柯萨奇B3病毒活性

3-硝基邻苯二甲酸酐经氨解、Hoffman降解、水合肼还原及闭环反应得2-芳基-1H-苯并咪唑-4-羧酸,经氯化亚砜酰氯化后与相应的胺反应,制得2-取代芳基-1H-苯并咪唑-4-酰胺类衍生物1a～1g,均为新化合物.并测定了其抑制柯萨奇B3病毒(CVB3)活性.结果显示,化合物1b、1c、1e和1g的活性优于利巴韦林.     

含二茂铁基Schiff碱类化合物的设计、合成及抗真菌活性研究

目的合成一系列含二茂铁基的Schiff碱类化合物,并测定其体外抗真菌活性。方法以二茂铁为起始原料,经乙酰化、氧化、酰化、肼解制得中间体二茂铁甲酰肼(1);以各种4-取代的苯硫酚和3-氯丙酸为起始原料,经取代、环合制得中间体取代2H-苯并[b]噻喃-4-酮(2a);以取代苯酚和3-氯丙酸为起始原料,经加成、环合制得中间体取代2H-苯并[b]吡喃-4-酮(2b);以各种取代苯胺和丙烯酸为起始原料,经加成、环合制得中间体取代2,3-二氢喹啉-4(1H)-酮(2c),中间体2a、2b、2c分别与1反应得到目标化合物。采用二倍浓度稀释法测试各目标化合物的体外抗真菌活性。结果与结论合成的15个化合物均未见文献报道,其结构经1H-NM R、HRM S谱确证;活性测试结果表明,多个目标化合物对测试真菌表现出一定的体外抑菌活性。     

4-氯苯甲酸取代马蹄金素衍生物的合成及其抗HBV活性研究

目的设计和合成含4-氯苯甲酸取代马蹄金素(Matijin-Su,MTS)衍生物,以期寻找到抗乙肝病毒(HBV)活性更强的MTS衍生物。方法以马蹄金素为先导化合物,通过引入4-氯苯甲酸取代,设计合成一系列MTS衍生物并对其进行抗HBV活性测试。结果设计合成了4-氯苯甲酸取代的MTS衍生物11个(3、4a、4b、4c、4d、4e、4f、4g、4h、4i、5),其中化合物4b、4d、4e、4h表现出良好的抗HBV活性,IC50分别为9.19、15.30、13.48、14.90μmol·L~(-1)。结论 4-氯苯甲酸取代的MTS衍生物具有更强的抗HBV活性,具有进一步研究的价值。     

阿魏酰胍丁胺类似物的设计、合成及Na~+/H~+交换器-1抑制活性

为了寻找新结构类型的Na+/H+交换器-1(NHE-1)抑制剂,以阿魏酸、胍丁胺为先导化合物,设计并合成了9个阿魏酰胍丁胺类似物。其结构经1H NMR、13C NMR和MS确证,其中化合物5f～5i为新化合物。初步的药理实验结果表明,部分目标化合物显示出较好的NHE抑制活性,其中化合物5a、5b和6c对NHE-1的抑制活性明显优于阳性对照药卡立泊来德(cariporide)。     

2-甲基-2-取代-7-羟基-2,3-二氢-4H-1-苯骈吡喃-4-酮及其衍生物的合成和抗真菌活性研究

目的：对自行设计的抗真菌先导化合物进行衍生物合成和抗真菌活性研究,以验证设计思想,检验模建结果的可靠性。方法：设计合成18个化合物,所有目标化合物经元素分析、¹HNMR谱和红外光谱确证,部分化合物还进一步用¹³CNMR谱、MS-EI谱和高分辨质谱确证。用8种人类致病真菌对所有目标化合物测试体外最小抑菌浓度值。结果：合成的18个化合物中,14个(JS1b～d,JS2a～d,JS3a～b,JS4a～d和JS5c)为新化合物。结论：对所合成的化合物进行抗真菌活性测试,结果表明设计合成的衍生物的抗真菌活性变化规律与设计思想吻合,从配体角度验证了模建的靶酶三维结构的可靠性,检测了活性位点力场的分布。     

黄酮衍生物的合成及其抗炎活性研究

目的 设计合成一系列黄酮衍生物,并考察其抗炎活性。方法 采用Baker-Venkataraman反应合成单羟基取代的黄酮,进而经Williamson反应合成黄酮衍生物;以布洛芬为阳性对照药,采用巴豆油致小鼠耳肿胀实验对5个目标化合物（1a、1c、1d、2a、2c）的抗炎活性进行了评价。结果与结论 以2’,5’-二羟基苯乙酮或2’,4’-二羟基苯乙酮为原料,合成了12个未见文献报道的新化合物,其结构经核磁共振氢谱、高分辨质谱及红外光谱确证。初步的药理筛选结果表明化合物6-[2-(4-吗啉基)乙氧基]黄酮(1a)和2’-氟-7-(2-二甲氨基甲酰甲氧基)黄酮(2c)具有潜在的抗炎活性。     

太平洋侧花海葵中四个新神经酰胺的鉴定

目的研究太平洋侧花海葵(Anthopleura pacifica)中的生物活性成分.方法采用稻瘟霉模型生物活性追踪方法,应用色谱技术进行分离,根据理化性质和波谱分析鉴定结构.结果得到了1个对稻瘟霉显示活性的组分,并鉴定为4个神经酰胺的混合物:N-羟乙基-N-十四酰-(2S,3R)-十八碳鞘氨醇-4(E),8(E)-二烯(a),N-羟乙基-N-(9Z-十六烯酰)-(2S,3R)-十八碳鞘氨醇-4(E),8(E)-二烯(b),N-羟乙基-N-十六酰-(2S,3R)-十八碳鞘氨醇-4(E),8(E)-二烯(c)和N-羟乙基-N-(13Z-二十二烯酰)-(2S,3R)-十八碳鞘氨醇-4(E),8(E)-二烯(d).结论化合物a～d均为新的神经鞘氨醇化合物.     

新型卤酚类化合物的合成及其体外抗氧化活性研究

目的 合成具有新型结构的系列卤酚类化合物,测定其体外抗氧化活性并初步探讨其构效关系。 方法 以取代苯甲酸或苯甲酰氯为原料,经多步反应制得卤酚类化合物,并通过DPPH（二苯代苦味肼基）自由基清除实验测定其抗氧化活性。 结果与结论 9个目标化合物均为首次合成的新化合物,其结构经ESI-MS、1H-NMR、13C-NMR确证,总收率70%~91%。体外活性实验表明,抗氧化活性与羟基和卤原子的数目与位置有关;化合物5c,5c’,8b,8c的抗氧化活性优于常用抗氧化剂BHT（二丁基羟基甲苯）。     

新3,5-二取代唑烷酮抗菌剂的合成及其体外抑菌活性新3,5-二取代唑烷酮抗菌剂的合成及其体外抑菌活性

目的设计、合成唑烷酮新化合物并测定其体外抑菌活性。方法对文献方法进行了改进，在文献报道的构效关系基础上，设计、合成唑烷酮新化合物并测定体外抑菌活性。结果合成了39个新化合物，其中目标物18个，其结构经IR,¹HNMR,MS等方法确证。16个化合物显示出较好的抑菌活性，其中化合物9，10，10b对4种试验菌的MIC50和 MIC90值小于或接近4种对照药，化合物9a和11c没有抑菌活性。结论化合物9，10和10b值得进一步研究。     

4-(2-乙酰氧基苯甲酰氨基)丁酸酯类化合物的设计、合成及抗癫痫活性研究

以中枢抑制性神经递质γ-氨基丁酸(GABA)受体调节位点为靶点,以GABA(1)为原料设计合成了12个未见文献报道的4-(2-乙酰氧基苯甲酰氨基)丁酸及酯类化合物(7a～7k)。目标化合物经IR、1H MNR、EI-MS及元素分析确证了结构。初步体外活性表明,所合成的化合物具有不同程度的抗癫痫活性,其中化合物7i～7k具有很好的抗癫痫活性,值得进一步研究,化合物4、7d～7h显示较好的抗癫痫活性。在此基础上,初步讨论了该类化合物的构效关系。     

Unsaturated and carbocyclic nucleoside analogues: synthesis, antitumor, and antiviral activity

A series of unsaturated analogues of nucleosides were prepared and their cytotoxic, antitumor, and antiviral activities were investigated. Alkylation of cytosine with (E)-1,4-dichloro-2-butene gave chloro derivative 2f, which was hydrolyzed to alcohol 2h. Cytosine, adenine, 2-amino-6-chloropurine, thymine, and (Z)-1,4-chloro-2-butene gave compounds 4c-f, which, after hydrolysis, afforded alcohols 4a, 4b, 4g, and 4h. Alkenes 4d and 4e were cyclized to heterocycles 12 and 13. Alkylation of 2,6-diaminopurine with 1,4-dichloro-2-butyne led to chloro derivative 6a, which was hydrolyzed to alcohol 6b. Allenic isomerization of 6b gave compound 5c. Chloro derivatives 2e-g, 4c-f, 5d, and 6c-e as well as pyrimidine oxacyclopentenes 9c and 9d are slow-acting inhibitors of murine leukemia L1210 of IC50 10-100 microM. The most active were analogues 4c, 4d, 4e, and 6e (IC50 10-20 microM). The corresponding hydroxy derivatives were less active of inactive. Inhibition of macromolecular synthesis with compounds 4c, 4d, 6e, 9c, and 9d follows the order: DNA greater than RNA greater than or equal to protein. Cytotoxic effects of 4c, 6e, and 9d are not reversed with any of the four basic ribonucleosides or 2'-deoxyribonucleosides. Inhibitory activity of cytosine derivative 9c is reversed with uridine and 2'-deoxyuridine but not with the corresponding cytosine nucleosides. Zone assays in several tumor cell lines show that active compounds are cytotoxic agents with little selectivity for tumor cells. Analogue 6c showed 16.7% ILS in leukemia P388/o implanted ip in mice at 510 and 1020 mg/kg, respectively. Cytallene (5b) and 6'beta-hydroxyaristeromycin (10) exhibited significant activity against Friend and Rauscher murine leukemia viruses. The rest of the hydroxy derivatives, with the exception of 4a, were moderately effective or inactive as antiviral agents. None of the chloro derivatives or oxacyclopentenes exhibited an antiviral effect at noncytotoxic concentrations. Z-Olefin 4b and 2-aminoadenallene (5c) are substrates for adenosine deaminase.     

Synthesis of benzylated amine-substituted xanthone derivatives and their antioxidant and anti-inflammatory activities

Oxidative stress and its constant companion, inflammation, play a critical part in the pathogenesis of many acute and chronic illnesses. The discovery of new multi-targeted drug candidates with antioxidant and anti-inflammatory properties is deemed necessary. Thus, a series of novel xanthone derivatives with halogenated benzyl ( 4b – 4d , 4f – 4h ) and methoxylated benzyl groups ( 4e ) attached to the butoxy amine substituent were synthesized in this study. The synthesized xanthone derivatives exhibited stronger antioxidant activity against H₂O₂ scavenging than the standard drug, α-tocopherol, but weaker towards DPPH scavenging and ferrous ion chelation. Besides that, 4b – 4d , 4f – 4h demonstrated good anti-inflammatory activities through NO production inhibition towards lipopolysaccharide (LPS)-induced RAW 264.7 cells and showed 2–4 times stronger effects than the standard drug, diclofenac sodium. Moreover, compound 4b with two brominated benzyl groups attached to the butoxy amine substituent suppressed the production of pro-inflammatory cytokines, TNF-α and IL-1β, significantly. Structure–activity relationship elucidated that the halogenated benzylamine substituent plays an important role in contributing the antioxidant and anti-inflammatory activities of xanthones. In summary, xanthone 4b was identified as a potential lead compound to be further developed into antioxidant and anti-inflammatory drugs. Thus, further studies on the related mechanisms of action of 4b are recommended.     

In vitro evaluation on the antioxidant capacity of triethylchebulate, an aglycone from Terminalia chebula Retz fruit

Objectives:

To evaluate the antioxidant and free-radical scavenging activities of triethylchebulate (TCL), an aglycone isolated from the fruit of Terminalia chebula Retz.

Materials and Methods:

Microsomes, mitochondria and red blood cells (RBCs) were isolated from rat liver. The antioxidant capacities were evaluated by determining the inhibitory effects of TCL on lipid peroxidation, hydrogen peroxide (H₂O₂)-induced RBCs hemolysis and RBCs autoxidative hemolysis. The free-radical scavenging activities were evaluated by 1,1-diphenyl-2-picrylhydrazyl (DPPH) method and 2´,7´-dichlorodihydrofluorescin diacetate (DCFH₂-DA) assay.

Result:

TCL significantly inhibited FeSO₄/Cys-induced microsomes lipid peroxidation and protected both H₂O_2--induced RBCs hemolysis and RBCs auto-hemolysis in a dose-dependent manner. Furthermore, TCL demonstrated potent DPPH free-radical scavenging ability with IC₅₀ at 2.4×10^-5 M. In addition, TCL also moderately suppressed azide-induced mitochondria ROS formation.

Conclusion:

These results demonstrated that TCL was a strong antioxidant and free-radical scavenger, which might contribute to the anti-oxidative ability of Terminalia chebula Retz.     

PEG Mediated Synthesis and Biological Evaluation of Asymmetrical Pyrazole Curcumin Analogues as Potential Analgesic,Anti-Inflammatory and Antioxidant Agents

The new series of asymmetrical pyrazole curcumin analogues 4a – g were synthesized by using polyethylene glycol (PEG-400) as a green reaction medium and evaluated for their in vivo analgesic and in vitro antioxidant (H₂O₂, DPPH, Ferrous reducing power and Nitric oxide scavenging activity) and anti-inflammatory activities. All the compounds synthesized 4a – g showed the potential to demonstrate analgesic activity as compared to the standard ibuprofen. Among the tested series, compounds 4e and 4b exhibited good hydrogen peroxide scavenging activity as compared to the standard butylated hydroxy toluene (BHT). Compounds 4b , 4d , 4f , and 4g showed good DPPH free radical scavenging activity. Compounds 4b , 4c , 4d , 4e and 4g showed excellent ferrous-reducing power activity, whereas all the compounds showed better nitric oxide scavenging activity than standard ascorbic acid. Additionally, all the synthesized compounds were also screened for their in vitro anti-inflammatory activity. Compounds 4b , 4d , 4f and 4g showed good anti-inflammatory activity as compared to standard diclofenac sodium.     

Mephedrone, compared with MDMA (ecstasy) and amphetamine, rapidly increases both dopamine and 5-HT levels in nucleus accumbens of awake rats

BACKGROUND AND PURPOSE

The designer drug 1-(4-methylphenyl)-2-methylaminopropan-1-one (4-methylmethcathinone, mephedrone) is reported to possess psychostimulant, entactogenic and hallucinogenic effects. The purpose of this study was to examine the effects of acute administration of mephedrone on extracellular levels of dopamine (DA) and 5-HT in the nucleus accumbens of awake rats and compare these effects with those induced by 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) and amphetamine.

EXPERIMENTAL APPROACH

Microdialysis sampling was performed while simultaneously recording locomotor activity in rats and the monoamines were determined by HPLC with electrochemical detection.

KEY RESULTS

Mephedrone (3 mg·kg⁻¹ s.c.) and (+)-amphetamine (1 mg·kg⁻¹ s.c.) caused rapid increases in extracellular DA levels of 496% and 412%, respectively, whereas MDMA (3 mg·kg⁻¹ s.c.) showed only a moderate effect (235%). The corresponding 5-HT levels increased to 941% (mephedrone) and 911% (MDMA), but only to 165% following amphetamine. The calculated t_1/2 values for elimination rate of mephedrone, MDMA and amphetamine-induced increases in extracellular DA levels were 25, 303 and 51 min, the corresponding t_1/2 values for 5-HT were 26, 48 and 84 min, respectively. Locomotor activity was increased most by amphetamine, whereas both mephedrone and MDMA showed about three times lower and shorter-lasting effects.

CONCLUSIONS AND IMPLICATIONS

The neurochemical and functional properties of mephedrone resemble those of MDMA, but it also shows an amphetamine-like effect in that it evokes a rapid release and elimination of DA in the brain reward system, a feature that may contribute to its potent re-inforcing properties.     

Release of ATP from rat urinary bladder mucosa: role of acid,vanilloids and stretch

Background and purpose:

ATP, released from urothelial cells, modulates afferent nerve firing from the urinary bladder. Here, we have characterized ATP release from the rat bladder mucosa in response to acid, capsaicin, electrical field stimulation (EFS) and stretch, using agonists and antagonists at transient receptor potential vanilloid receptor 1 (TRPV1) and acid-sensing ion channels (ASICs).

Experimental approach:

Rat mucosal strips (containing urothelium and lamina propria) in Perspex microbaths were superfused with Krebs solution. ATP was measured after exposure of matched strips to acid (pH 6.6–5.0), capsaicin (0.1–10 µM), EFS or stretch (150% of original length).

Key results:

Median basal ATP release was 3.46 nmol·g⁻¹. The mucosal strips responded to stimuli with potency order (median, IQR): acid (pH 5.6–6.0) 286 (103–555) > 10 µM capsaicin 188 (117–431) > 10 Hz EFS 63.0 (13.3–96.4) > stretch 24.4 (6.73–55.1) nmol ATP g⁻¹. ATP release in response to acid was pH dependent (P < 0.05). Responses to capsaicin did not desensitize nor were they concentration dependent. TRPV1 antagonist, capsazepine (10 µM) abolished capsaicin-evoked ATP release, and reduced acid-evoked (pH 6.5) release to 30% (P < 0.001). The ASIC channel antagonists gadolinium (0.1 mM) and amiloride (0.3 µM) reduced (P < 0.05) the acid-evoked (pH 6.5) release to 40 and 6.5% respectively. ASIC (ASIC1, ASIC2a, ASIC2b, ASIC3) and two TRPV1 gene products were detected in mucosal and detrusor extracts.

Conclusions and implications:

Capsaicin (at TRPV1) and acid (at both TRPV1 and ASIC) induce ATP release from the rat bladder mucosa. This ATP appears to be principally of urothelial origin. This study highlights the importance of ATP and acid as signalling molecules in modulating bladder function.     

The antiepileptic effect of Centella asiatica on the activities of Na+/K+, Mg2+ and Ca2+-ATPases in rat brain during pentylenetetrazol�Cinduced epilepsy

Background:

To study the anticonvulsant effect of different extracts of Centella asiatica (CA) in male albino rats with reference to Na⁺/K⁺, Mg²⁺ and Ca²⁺-ATPase activities.

Materials and Methods:

Male Wistar rats (150±25 g b.w.) were divided into seven groups of six each i.e. (a) control rats treated with saline, (b) pentylenetetrazol (PTZ)-induced epileptic group (60 mg/kg, i.p.), (c) epileptic group pretreated with n-hexane extract (n-HE), (d) epileptic group pretreated with chloroform extract (CE), (e) epileptic group pretreated with ethyl acetate extract (EAE), (f) epileptic group pretreated with n-butanol extract (n-BE), and (g) epileptic group pretreated with aqueous extract (AE).

Results:

The activities of three ATPases were decreased in different regions of brain during PTZ-induced epilepsy and were increased in epileptic rats pretreated with different extracts of CA except AE.

Conclusion:

The extracts of C. asiatica, except AE, possess anticonvulsant and neuroprotective activity and thus can be used for effective management in treatment of epileptic seizures.     

Novel ketoprofen–antioxidants mutual codrugs as safer nonsteroidal anti‐inflammatory drugs: Synthesis,kinetic and pharmacological evaluation

Ketoprofen belongs to one of the most common nonsteroidal anti‐inflammatory drugs (NSAIDs) but its clinical usefulness has been restricted due to the high incidence of gastrointestinal complications. The release of reactive oxygen species (ROS) in NSAIDs therapy plays a major role in causing gastric complications. Antioxidants not only prevent gastric ulceration and lipid peroxidation but also preserve glutathione‐type peroxidase (GPO) activity. Therefore, the present study investigates the utility of combining anti‐inflammatory and antioxidant properties of two different compounds in a single molecule to form a series of 16 ketoprofen–antioxidant mutual codrugs. The free carboxylic group, which is believed to be one of the reasons for gastric toxicity of ketoprofen, was masked temporarily by simple and double esterification with alcoholic/phenolic–OH of natural antioxidants. In simple esterification, ketoprofen is directly linked to natural antioxidants ( IIa–h ) in the hope to obtain drugs free of gastric side effects. In an attempt to improve the in vivo lability, as well as gastric side effects, the double ester codrugs, that is, ketoprofen–antioxidant through the glycolic acid spacer (–CH₂COO; IIIa–h ), have also been designed and synthesized. The synthesized codrugs were characterized by IR, ¹H NMR, ¹³C NMR, mass spectroscopy and elemental analysis. The in vitro hydrolysis studies showed the lowest hydrolysis (highest stability) in acidic pH 1.2, whereas moderate hydrolysis was seen at pH 7.4 and significant hydrolysis in 80% human blood plasma, as indicated by their t_1/2. The pharmacological evaluation results indicate that these ketoprofen–antioxidant mutual codrugs showed the retention of anti‐inflammatory and analgesic activity with a significant reduction in the ulcer index.     

Violence among men and women in substance use disorder treatment: A multi-level event-based analysis

Background

This study examined associations between acute alcohol and drug use and violence towards others in conflict incidents (overall, partner, and non-partner conflict incidents) by men and women recruited from substance use disorder (SUD) treatment.

Methods

Semi-structured interviews were used to obtain details about interpersonal conflict incidents (substance use, whether specific conflicts were with intimate partners or non-partners) in the 180 days pre-treatment. Participants for this study were selected for screening positive for past-year violence (N = 160; 77% men, 23% women).

Results

Multi-level multinomial regression models showed that after adjusting for clustering within individual participants, the most consistent predictors of violence across models were acute cocaine use (significant for overall, intimate partner and non-partner models), acute heavy alcohol use (significant for overall and non-partner models), and male gender (significant in all models).

Conclusions

This study was the first to explicitly examine the role of acute alcohol and drug use across overall, partner and non-partner conflict incidents. Consistent with prior studies using a variety of methodologies, alcohol, cocaine use and male gender was most consistently and positively related to violence severity (e.g., resulting in injury). The results provide important and novel event-level information regarding the relationship between acute alcohol and specific drug use and the severity of violence in interpersonal conflict incidents.     

Bis selenide alkene derivatives: A class of potential antioxidant and antinociceptive agents

Bis and tris-selenide alkene derivatives, a class of organoselenium compounds, were screened for antinociceptive and antioxidant activities. In vitro, bis-selenide alkene 1c (R=2,4,6-Me(3)C(6)H(2)), 1d (R=4-ClC(6)H(4)) and 1e (R=4-MeOC(6)H(4)) protected against lipid peroxidation about 50%, whereas 1b (R=C(6)H(5)) and 1a (R=C(4)H(9)) protected only 23%. Compound 1d presented lesser IC(50) against lipid peroxidation than other bis-selenide alkene compounds (1d>1e> or =1c>1a=1b). The maximal inhibitory effect of tris-selenide alkenes on lipid peroxidation was in the following order 2c>2a=2b. Compound 1e increased the rate of GSH, but not DTT, oxidation. Tris-selenide alkene 2c (R=4-MeOC(6)H(4)) demonstrated the higher rate of thiol oxidation, while 2a (R=C(6)H(5)) did not change DTT oxidation but oxidized GSH. Conversely, compound 2b (R=4-ClC(6)H(4)) did not change the rate of GSH oxidation, but oxidized DDT. Bis-selenide alkene derivatives 1c, 1d and 1e were the most promising compounds tested in vitro. In vivo, compounds 1c and 1d (5-50mg/kg, subcutaneously) produced significant inhibition of acetic acid- and capsaicin-induced pain. Compounds 1c and 1d increased the tail-flick response latency time. The antinociception effect of 1c and 1d was not abolished by naloxone (an antagonist of opioid receptor, 1mg/kg, subcutaneously), suggesting that the antinociceptive effect is not influenced by the opioidergic mechanism.