1-(1-phenethylpiperidin-4-yl)-1-phenylethanols as potent and highly selective 5-HT2A antagonists

The discovery of a novel class of highly potent and selective 5-HT2A antagonists is reported herein. Selectivity for the serotonin 5-HT2A receptor was optimized, decreasing the affinity of these antagonists toward the adrenergic alpha1 and dopaminergic D2 receptors, and especially to the 5-HT2C receptor. A series of corresponding 7-substituted indoles is described for the first time as serotonergic ligands. The enantiomer R-(+)-1-(4-fluorophenyl)-1-{1-[2-(4-fluorophenyl)ethyl]piperidin-4-yl} ethanol (R-(+)-74) was identified to have superior affinity for the serotonergic 5-HT2A receptor [IC50=0.37 nM] and selectivity toward the dopaminergic D2- [IC50=2300 nM], adrenergic alpha1- [IC50=1000 nM] and 5-HT2C receptors [IC50=490 nM].     

On the way to selective PARP-2 inhibitors. Design, synthesis, and preliminary evaluation of a series of isoquinolinone derivatives

PARP-1 and PARP-2 are members of the family of poly(ADP-ribose)polymerases, which are involved in the maintenance of genomic integrity under conditions of genotoxic stimuli. The different roles of the two isoforms under pathophysiological conditions have not yet been fully clarified, and this is partially due to the lack of selective inhibitors. We report herein the synthesis and preliminary pharmacological evaluation of a large series of isoquinolinone derivatives as PARP-1/PARP-2 inhibitors. Among them, we identified the 5-benzoyloxyisoquinolin-1(2 H)-one derivative as the most selective PARP-2 inhibitor reported so far, with a PARP-2/PARP-1 selectivity index greater than 60.     

Design, synthesis, and in vitro antibacterial activity of fluoroquinolone derivatives containing a chiral 3-(alkoxyimino)-2-(aminomethyl)azetidine moiety

A series of novel (R)/(S)-7-(3-alkoxyimino-2-aminomethyl-1-azetidinyl)fluoroquinolone derivatives were synthesized and evaluated for their in vitro antibacterial activity against representative strains. Our results reveal that 12 of the target compounds generally show better activity (MIC: <0.008-0.5 μg mL(-1)) against the tested Gram-positive strains including MRSA and MRSE than levofloxacin (LVFX, MIC: 0.125-8 μg mL(-1)). Their activity is similar to that of gemifloxacin (GMFX, MIC: <0.008-4 μg mL(-1)). However, they are generally less active than the two reference drugs against Gram-negative strains. Moreover, against clinical strains of S. aureus including MRSA and S. epidermidis including MRSE, the MIC(50) values (0.06-16 μg mL(-1)) and MIC(90) values (0.5-32 μg mL(-1)) of compounds 16 w, y, and z are 2-8- and 2-16-fold less than LVFX, respectively, and 16 w (MIC(90) range: 0.5-4 μg mL(-1)) was also found to be more active than GMFX (MIC(90) range: 1-8 μg mL(-1)).     

Synthesis,characterization and antibacterial activity of Pd(II), Pt(II) and Ag(I) complexes of 4-ethyl and 4-(p-tolyl)-1-(pyridin-2-yl)thiosemicarbazides

Pd(II), Pt(II) and Ag(I) ions were found to form stable complexes with 4-(p-tolyl)- or 4-ethyl-1-(pyridin-2-yl)thiosemicarbazides (Hp-TPTS or HEPTS). The complex structure was elucidated by analysis (elemental and thermal), spectroscopy (electronic, IR and ¹H NMR spectra) and physical measurements (magnetic susceptibility and molar conductance). The ligands coordinate to the metal ions as monobasic bidentate through nitrogen and sulfur atoms. The electronic spectra of the Pt(II) complexes in DMF showed a metal to ligand charge transfer transition at 11,935–13,260 cm^?1. The structural, electronic and vibrational features of HEPTS and Hp?TPTS were discussed on the basis of semi-empirical quantum mechanic calculations [ZINDO/S and semi-empirical parameterization (PM3)]. The simulated IR and electronic spectra are found reasonable in accordance with the experimental data. Finally, the antibacterial activities of the ligands and their complexes were investigated and some were found promising.     

Synthesis, characterization and biological activity of trans-platinum(II) and trans-platinum(IV) complexes with 4-hydroxymethylpyridine

The synthesis and chemical characterization of two new trans platinum complexes, trans-[PtCl(2)NH(3)(4-hydroxymethylpyridine)] (1) and trans-[PtCl(4)NH(3)(4-hydroxymethylpyridine)] (2) are described. Their ability to interact with 5'-GMP by themselves and in the presence of reducing agents in the case of trans-[PtCl(4)NH(3)(4-hydroxymethylpyridine)] were tested. Circular dichroism, electrophoretic mobility in agarose gel, and atomic force microscopy studies showed that the interaction of complex 1 with DNA is stronger than that of complex 2. Cytotoxicity tests against HL-60 tumor cells also showed higher activity for trans-[PtCl(2)NH(3)(4-hydroxymethylpyridine)] than for trans-[PtCl(4)NH(3)(4-hydroxymethylpyridine)]. Complex 1 presents similar behavior to cisplatin, but with a lower IC(50) at 24 h. Complex 1 also showed high apoptosis induction.     

Synthesis,molecular docking and antibacterial evaluation of 2-(4-(4-aminophenylsulfonyl)phenylamino)-3-(thiophen-2-ylthio)naphthalene-1,4-dione derivatives

A new series of 2-(4-(4-aminophenylsulfonyl)phenylamino)-3-(thiophen-2-ylthio)naphthalene-1,4-dione derivatives (3a-3n) were synthesized and characterized by spectral techniques. To understand the interaction of binding sites with bacterial protein receptor, the docking study was performed by the GLIDE program and compound N-(4-(4-(1,4-dioxo-3-(thiophen-2-ylthio)-1,4-dihydronaphthalen-2-ylamino)phenylsulfonyl)phenyl)-3-methylbenzamide (3b) exhibited good glide and E model scores of ?5.89 and ?94.90, respectively. Moreover among all the molecules studied including the standards used, namely Sparfloxacin (4.8 μg/mL) and Norfloxacin (no inhibition observed) for their antibacterial property, compound N-(4-(4-(1,4-dioxo-3-(thiophen-2-ylthio)-1,4-dihydronaphthalen-2-ylamino)phenylsulfonyl)phenyl)-4-nitrobenzamide (3e) exhibited the lowest minimum inhibitory concentration (MIC) value of 1.3 μg/mL against Proteus vulgaris.     

(-)-1R,2S,5R-8-(4-溴苯)薄荷醇的合成与表征

以R-( )-长叶薄荷酮为起始原料,经1,4-加成、还原、溴代、水解等4步反应合成了标题化合物,总产率77%。其结构用1HNMR、13CNMR和IR进行了表征。     

Synthesis and evaluation of biological activities of 4-cyclopropyl-5-(2-fluorophenyl) arylhydrazono-2,3-dihydrothiazoles as potent antioxidant agents

A new series of 4-cyclopropyl-5-(2-fluorophenyl)arylhydrazono-2,3-dihydrothiazole derivatives was synthesized via the reaction of prepared thiosemicarbazones with 2-bromo-1-cyclopropyl-2-(2-?uorophenyl)ethanone in the presence of Et₃N as a catalyst through a semi Hantzsch cyclization. The optimized reaction conditions for this one-pot reaction were achieved. The products were obtained in short reaction times, high yields and high purities. Antioxidant activity of products was evaluated using DPPH (2,2-diphenyl-2-picrylhydrazyl) and ABTS 2,2-azinobis(3-ethylbenzothiazoline-sulfonate) assays. Products showed higher antioxidant activity using the ABTS method. Compounds 5c and 5g showed lower IC₅₀ values compared with ascorbic acid as a standard. Compounds 5a–5h possessed moderate to high antioxidant activity by both methods. Also, antibacterial activity of 5a–5h was evaluated against gram-positive and gram-negative bacterial strains. None of the compounds inhibited A. hydrophila, while they had moderate to low inhibitory activity against other tested bacterial strains.     

(2S,3R)-2-羟基-3-氨基-4-苯基丁酸的合成方法进展

(2S,3R)-2羟基-3-氨基-4-苯基丁酸（AHPBA）是制备Bestatin、Phebestin和Probestin等氨肽酶N(Aminopeptide N)抑制剂的关键中间体。本文从氨基酸法（D-苯丙氨酸、L-天门冬氨酸、苹果酸二酯）、有机金属催化法（双功能铝配合物）、酶催化法（脂肪酶和全细胞酶）以及其它方法对此中间体的合成方法及路线进行综述和分析。经比较,有机催化法、酶法以及苯乙酮法因其具有经济有利、条件温和或路线简单特点,具有潜在的工业化应用前景。同时,未来人们对AHPBA的合成开发将集中在对已有工艺路线的改进与优化。     

13-cis-维A酸-5-氟尿嘧啶酯的合成、表征及其活性研究

在比较DCC-DMAP和HMPA两种不同合成方法的基础上,在室温下顺利地将在通常反应条件下极易异构化的13-cis-维A酸合成了其衍生物13-cis-维A酸-N1-(2-四氢呋喃烷基)-N3-乙基-5-氟尿嘧啶酯(5,RAFU),其结构通过1HNMR、13CNMR和MS进行了表征。生物活性测试表明,该化合物对肝癌细胞、舌癌细胞等癌细胞都具有抗癌活性。     

Design, synthesis, and biological evaluation of 1-[(biarylmethyl)methylamino]-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ols as potent antifungal agents: new insights into structure-activity relationships

We recently reported the design and synthesis of azole antifungal agents with a focus on modifications to the side chain appended to the propanol group. Herein we have identified a series of new 1-[(biarylmethyl)methylamino] derivatives with broad-spectrum antifungal activities against the most prevalent human pathogenic fungi (Candida spp. and Aspergillus fumigatus). Compounds containing a flexible benzylamine moiety were clearly shown to yield the best antifungal activities, without the need for a hydrogen-bond acceptor substituent directly attached to the para position. We were also able to determine that selected compounds are able to overcome gene overexpression and point mutations that lead to reduced susceptibility or resistance against current treatments, such as fluconazole. As the minor differences observed with small structural modifications cannot be explain with only a three-dimensional model of CYP51, adequate physicochemical parameters must be evaluated in terms of antifungal potency, bioavailability, and toxicity. Therefore, structure-activity relationship studies such as these reveal new insights for the development of future antifungal therapies.     

4-[2-(4,6-二甲氧基嘧啶基)]-3-硫代脲酸苯酯合成工艺及生物活性研究

采用二步反应考察了4-[2-(4,6-二甲氧基嘧啶基)]-3-硫代脲酸苯酯合成的最优反应条件,通过氢谱(1H NMR)、红外光谱(IR)、元素分析和熔点测定,对所合成的产物进行结构分析。采用离体含毒介质法,对合成产物进行杀菌毒力活性的测定。结果表明,0.1 mol氯甲酸苯酯和0.2 mol硫氰酸钾,在乙酸乙酯中50℃反应2 h,滤去生成的氯化钾,加入4,6-二甲氧基嘧啶-2-胺0.08 mol,在60℃下反应4 h,产品总得率不低于75%。产品对植物病害菌有良好的抑制和杀灭作用。     

立体选择性合成（S，S）－2－羟基－3－氨基－4－苯基丁酸

研究了药物及其中间体的立体选择性合成。报道了一种抗艾滋病候选药中间体（Ｓ，Ｓ）－２－羟基－３－氨基－４－笨基丁酸的立体选择性合成方法，显著地提高了Ｓ－型产物的收率。     

新型先导化合物2-(2-氯-4-三氟甲基苯氧基)-4-三氟甲基噻唑-5-甲酸乙酯的设计、合成与生物活性

以3-氨基-4,4,4-三氟甲基丁烯酸乙酯为原料,经环化、氯化、醚化制得新型先导化合物2-（2-氯-4-三氟甲基苯氧基）-4-三氟甲基噻唑-5-甲酸乙酯,其结构经红外、核磁、高分辨质谱确认。生物活性测定结果表明新型先导化合物在600g／hm^2剂量下对叶蝉和二点叶螨的防效均为100％;在300g／hm^2剂量下对马铃薯晚疫病的防效为90％。     

Voltammetric studies of a cobalt(II)-4-methylsalophen modified carbon-paste electrode and its application for the simultaneous determination of cysteine and ascorbic acid

A carbon-paste electrode (CPE) chemically modified with the cobalt(II)-4-methylsalophen (CoMSal) as a Schiff base complex was used as a highly sensitive and fairly selective electrochemical sensor for simultaneous determination of minor mounts of ascorbic acid (AA) and cysteine. This modified electrode shows very efficient electrocatalytic activity for anodic oxidation of both AA and cysteine via substantially decreasing of anodic overpotentials for both compounds. The mechanism of electrochemical oxidation of both AA and cysteine using CoMSal-modified electrode was thoroughly investigated by cyclic voltammetry and polarization studies. Results of cyclic voltammetry (CV) and differential pulse voltammetry (DPV) using this modified electrode show two well-resolved anodic waves for the oxidation of AA and cysteine, which makes it possible for simultaneous determination of both compounds. A linear range of 1 × 10⁻⁴ to 5 × 10⁻⁷ M for cysteine in a constant concentration of 1 × 10⁻⁴ M AA in buffered solution (as a background electrolyte) was obtained from DPV measurements using this electrode. The linear range, which is obtained for AA in the presence of 1 × 10⁻⁴ M cysteine, was in the range of 1 × 10⁻⁴ to 1 × 10⁻⁶ M. The modified electrode has good reproducibility (RSD ≤ 2.5%), low detection limit (sub-micromolar) and high sensitivity for the detection of both AA and cysteine with a very high stability in its voltammetric response. Differential pulse voltammetry using the modified electrode exhibited a reasonable recovery for a relatively wide concentration range of cysteine spiked to a synthetic human serum sample.     

Highly Efficient and Selective Transport of Cu(II) with a Cooperative Carrier Composed of Tetraaza-14-Crown-4 and Oleic Acid through a Bulk Liquid Membrane

Tetraaza-14-crown-4 and oleic acid was successfully applied for transport of Cu(II) in chloroform bulk liquid membrane. The uphill moving of Cu(II) during the liquid membrane transport process has occurred. The main effective variable such as the type of the metal ion acceptor in the receiving phase and its concentration, tetraaza-14-crown-4 and oleic acid concentration in the organic phase on the efficiency of the ion-transport system were examined. By using L-cysteine as a metal ion acceptor in the receiving phase, the maximum amount of copper (II) transported across the liquid membrane was achieved to 96 ± 1.5% after 140 minutes. The selectivity of copper ion transport from the aqueous solutions containing Pb²⁺, Tl⁺, Ag⁺, Co²⁺, Ni²⁺, Mg²⁺, Zn²⁺, Hg²⁺, Cd²⁺ and Ca²⁺ ions were investigated. In the presence of CH₃COONH₄ and Na₄P₂O₇ as suitable masking agents in the source phase, the interfering effects of Pb⁺² and Cd²⁺ were diminished drastically.