Studies on the chemical modification of monensin. III. Synthesis and sodium ion transport activity of macrocyclic monensylamino acid-1,29-lactones.

Monensylglycine (2a) was lactonized to macrocyclic monensylglycine-1,29-lactone (3a) by Corey's method. Lactonization of monensylamino acids (2b--d) to monensylamino acid-1,29-lactones (3b--d) was carried out by utilizing the template effect of K+ ion. Monobenzyl esters of dicarboxylic monensylamino acids (5e--f) also were lactonized followed by debenzylation to yield carboxylic monensylamino acid-1,29-lactones (3e--f). Sodium ion transport activity of monensin (1) and the lactones (3) was measured in a liquid membrane and in guinea pig erythrocyte membrane. Monensylaspartic acid-1,29-lactone (3e) exhibited 2.5 times higher activity than 1 in the liquid membrane. Monensylalanine-1,29-lactone (3b), monensylphenylalanine-1,29-lactone (3c), and monensyltyrosine-1,29-lactone (3d), having smaller Na+ ion transport activity than 3e, showed weak antibacterial activity, while 3e was inactive in biological tests, probably due to the lower lipophilicity.     

Studies on chemical modification of monensin IX. Synthesis of 26-substituted monensins and their Na+ ion transport activity.

The C-26 modified monensin derivatives, 26-O-benzoylmonensin (3), 26-O-benzylmonensin (4) and 26-phenylaminomonensin (5) were prepared from monensin (1). Na+ ion transport activity through biological membrane and antibacterial activity of 3-5 were evaluated and compared with the activities reported for a 26-phenylurethane derivative (2). Among these compounds, 5 showed the largest Na+ ion transport and antibacterial activities. In these compounds, the formation of head-to-tail hydrogen bonds was suggested to be an important factor for Na+ ion transport and antibacterial activities.     

Synthesis and antibacterial activity of Schiff bases of 5-substituted isatins

Based on the existing reports on the bioactive isatin derivatives, a number of Schiff bases were synthesized by reacting 5-substituted isatins with bioactive amines/hydrazides and their structures were confirmed using spectroscopic methods such as NMR, IR and mass spectrometry. Furthermore, Nbenzylation of isatin followed by the Schiff base formation furnished a new series of compounds(11a–13c) which allowed the analysis of the effect of isatin N-substitution on the bioactivity of the resulting compounds. The antibacterial activity of the synthesized derivatives was evaluated using a microtiter plate method on a series of gram positive and gram negative bacterial strains. Compounds 2d, 3b, 5c and 6a were among the most potent derivatives against Pseudomonas aeruginosa(MIC = 6.25 μg/m L).Analysis of the structure–activity relationship showed that the incorporation of(thio)urea-based Schiff bases lead to more potent derivatives with a broader spectrum of antibacterial activity. In addition,highly lipophilic compounds such as 11a–12c did not show any measurable antibacterial activity, which implies that an optimal lipophilicity might be an important requirement for the antibacterial activity of the studied isatins. Finally, the finding that hydantoin derivatives of N-benzylisatins(13a–13c) still exhibit some antibacterial activity prompted us to consider exploring the bioactivity of more diverse derivatives of isatin-aminohydantoin Schiff bases(compounds 1a–1d) in our future studies.     

Structure-activity relationship (SAR) studies on oxazolidinone antibacterial agents. 2. Relationship between lipophilicity and antibacterial activity in 5-thiocarbonyl oxazolidinones

5-Thiourea and 5-dithiocarbamate oxazolidinones were synthesized as a continuation of research on 5-thiocarbonyl oxazolidinone antibacterial agents considering the hydrophobic parameters of the molecule. The structure-activity relationship (SAR) study revealed that the antibacterial activity on 5-thiocarbonyl oxazolidinones was significantly affected by the lipophilicity, especially the calculated log P value and the balance between 5-hydrophilic (or hydrophobic) substituent and hydrophobic (or hydrophilic) substituents on the benzene ring. Some of 5-thiocarbonyl oxazolidinones were found to have good in vitro antibacterial activity against gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE).     

Design,synthesis, characterization and antimicrobial evaluation of some novel hydrazinecarbothioamide, 4-thiazolidinone and 1,2,4-triazole-3-thione derivatives

A series of novel hydrazinecarbothioamide ( 5a,c,f ), 4-thiazolidinone ( 6a - e ), and 1,2,4-triazole-3-thione ( 7a - d ) were designed and synthesized. The structural elucidations of the novel compounds were performed by IR, ¹H-NMR, ¹³C-NMR, mass and elemental analysis. All novel derivatives were evaluated for their antibacterial and antifungal activities against nine diverse microorganisms. According to the biological activity studies of the compounds, 6d , 7c and 7d displayed hope promising antibacterial activity. Furthermore, 6d displayed potent antifungal activity. Consequently, the obtained results revealed that 6d , 7c and 7d present a leading structure for future drug development due to its straightforward synthesis and relevant bioactivity.     

3-杂环硫亚甲基头孢菌素衍生物的半合成及抗菌活性研究

通过取代噁二唑硫酮、噻二唑硫酮及三唑硫酮分别和头孢菌素母体7-ACA反应,制得14种7-氨基-3-杂环硫亚甲基头孢菌素新母体2a-2n,用1-芳基-5-甲基-1H-1,2,3-三唑-4-甲酰氯与头孢菌素新母体缩合,制得2种新的7β-(1-芳基-5-甲基-1H-1,2,3-三唑-4-甲酰胺基)-3-(2-取代1,3,4-bI二唑-5-硫亚甲基)头孢菌素4c,4d.新化合物结构经元素分析、IR、¹HNMR及FAB-MS确认.初步体外抗菌结果表明,新母体化合物2对革兰氏阳性菌有抑制活性且在相同浓度下比7-ACA强20倍,而头孢菌素4c,4d对革兰氏阳性和阴性菌都有显著抑制活性.     

7-取代三唑硫乙氧基黄酮衍生物的合成及生物活性

7-羟基黄酮与过量1,2-二溴乙烷反应得到7-溴乙氧基黄酮,将其分别与3-取代-4-氨基-1,2,4-三唑-5-硫酮肉桂醛席夫碱、3-取代-4-苯基-5-巯基-1,2,4-三唑、3-(α-萘亚甲基)-5-巯基-1,2,4-三唑及3-巯基-5-氨基-1,2,4-三唑肉桂醛席夫碱反应,得到4类共16个7-三唑硫乙氧基黄酮类衍生物.采用红外光谱(IR)、核磁共振氢谱(1H NMR)、质谱(MS)及元素分析(EA)等方法对化合物的结构进行了确证.测定了目标化合物清除超氧自由基(O-·2)、羟自由基(·OH)和2,2-二苯基-1-苦味酰基自由基(DPPH·)的活性及总还原能力,并测定了其抗菌活性.结果表明,多数化合物在0.5 mg/m L浓度时具有抗DPPH·活性,其中7-(5-苯亚甲基-4-苯基烯丙亚胺基-1,2,4-三唑-3-硫乙氧基)黄酮(1i)活性较强;多数化合物表现了较好的抑菌活性,其中7-(5-苯亚甲基-4-苯基-1,2,4-三唑-3-硫乙氧基)黄酮(2c)对大肠杆菌、金黄色葡萄球菌和黑曲霉均具有较强的抑制作用.     

Synthesis and antinociceptive activity of orally active opioid peptides: improvement of oral bioavailability by esterification

To improve the oral bioavailability of a dermorphin tetrapeptide analog, N(alpha)-1-iminoethyl-Tyr-D-MetO-Phe-MebetaAla-OH (III), which has a potent analgesic activity after oral administration, various derivatives were synthesized to increase lipophilicity by esterification of the C-terminal carboxyl group and/or acylation of the phenolic hydroxyl group on Tyr1. Antinociceptive activity was evaluated after subcutaneous or oral administration using the mouse tail pressure test. As a result, increased antinociceptive activity after oral administration as well as an improved ED50(p.o.)/ED50(s.c.) ratio, which is an indicator of oral bioavailability, were found for some compounds. With regard to the improvement of bioavailability, derivatives with acylation of the phenolic hydroxyl group on Tyr1 showed better results than derivatives with esterification of the C-terminal carboxyl group. In particular, an ED50(p.o.)/ED50(s.c.) ratio equivalent to that of morphine was found for an acetylated derivative, N(alpha)-1-iminoethyl-Tyr(COMe)-D-MetO-Phe-MebetaAla-OH (7a), as well as for a methoxycarbonylated derivative, N(alpha)-1-iminoethyl-Tyr(CO2Me)-D-MetO-Phe-MebetaAla-OH (7l).     

Novel 1,3,4‐Oxadiazole Derivatives of Dihydropyrimidinones: Synthesis,Anti‐Inflammatory,Anthelmintic, and Antibacterial Activity Evaluation

The present study depicts synthesis of a series of some novel 5‐(5‐(aryl)‐1,3,4‐oxadiazol‐2‐yl)‐3,4‐dihydro‐6‐methyl‐4‐styrylpyrimidin‐2(1H)‐one derivatives. All the newly synthesized compounds were characterized by FTIR, ¹H NMR, ¹³C NMR, mass spectrometry, and elemental analysis. The compounds were evaluated for their in vivo anti‐inflammatory activity by the carrageenan‐induced rat paw edema method. The compounds were also screened for their anthelmintic activity on Indian earthworms and antibacterial activity against some gram positive and gram negative strains of bacteria. This pharmacological activity evaluation revealed that, among all the compounds screened, compounds 4b and 4c were found to have promising anti‐inflammatory activity. Interestingly, compounds 4b , 4c , and 4i exhibited appreciable anthelmintic property, while compounds 4c , 4g , and 4h showed leading antibacterial activity against the selected pathogenic strains of bacteria.     

Synthesis of 7-thio-substituted 4-oxoquinoline-3-carboxylic acids with antibacterial activity

A series of C-7 thio-substituted 1-cyclopropyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acids were prepared and tested for their antibacterial activity. Structure-activity relationships associated with the C-5 and C-7 substituents were discussed. Among the C-7 substituents including alkylthio, arylthio, heteroarylthio, and cyclic aminothio groups, a 2-aminoethylthio group was the best for enhancing in vitro antibacterial activity. The C-5 variants increased activity in the order OH less than F less than H less than NH2. Of compounds prepared in this work, 5-amino-7-(2-aminoethyl)thio-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4 -oxo-quinoline-3-carboxylic acid (18) was the most active.     

Studies on the chemical modification of monensin. II. Measurement of sodium ion permeability of monensylamino acids using sodium-23 nuclear magnetic resonance spectroscopy

A technique to assay Na+ ions in cells is presented. Intracellular and extracellular Na+ ions in a suspension of guinea pig erythrocytes were conveniently determined by using sodium-23 nuclear magnetic resonance (23Na-NMR), in combination with two anionic shift reagents: Dy(TTHA)3- and Dy(PPPi)2(7-). Monensin (1), monensylalanine (2b), monensylserine (2c), and monensylphenylalanine (2d) induced large increases of intracellular Na+ ion concentration ([Nain]), while monensylglycine (2a), monensyltyrosine (2e), monensylaspartic acid (2f), and monensylglutamic acid (2g) showed slight increases. The values of initial increasing rate (Vi) of 2a-g were much smaller than that of 1. This fact was probably due to the lower lipophilicity of 2a-g than 1, because a good correlation was observed between Vi and Rm50 values of 1 and 2a-g. This lower lipophilicity is a consequence of conformational differences between 1 and 2a-g.     

Synthetic antibacterials. VIII. 7-(1′-alkylhydrazino)-1,8-naphthyridines and related compounds

Synthesis and in vitro antibacterial activity of 7-(1′-alkylhydrazino)-1,8-naphthyridines related to nalidixic acid were investigated. Namely, treatment of 7-alkylamino-1-ethyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acids 1a-d with sodium nitrite in the presence of hydrochloric acid gave the 1-ethyl-1,4-dihydro-7-(N-nitrosoalkylamino)-4-oxo-1,8-naphthyridine-3-carboxylic acids 2a-d , which upon reacting with zinc dust in acetic acid gave the 7-(1′-alkylhydrazino)-1-ethyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacids 3a-d. The compound 3a was alternately obtained by the reaction of 7-chloro-1-ethyl-1,4-dihydro-4-oxo-1,8-naphth-yridine-3-carboxylic acid ( 4 ) with methylhydrazine. The reaction of 7-chloro-4-hydroxy-1,8-naphthyridine-3-carboxylic acid ( 5 ) with methylhydrazine gave the 4-hydroxy-7-(1′-methylhydrazino)-4-oxo-1,8-naphthyridine-3-carboxylic acid ( 6 ), which upon treatment with alkyl halides afforded the 1-alkyl-1,4-dihydro-7-(1′-methyl-hydrazino)-4-oxo-1,8-naphthyridines 3a and 3e-g. The reaction of the appropriate 3 with ketones gave the corresponding 7-(1′-methylalkylidenehydrazino)-1,8-naphthyridines 7a-c and 8a-b. Among the compounds prepared, certain 3 and 7 exhibited good activity against Gram-negative bacteria.     

Relationships between structure, retention and biological activity of some Schiff base ligands and their complexes

The lipophilicity of a series of Schiff base ligands and their complexes with nickel(II) and copper(II) has been determined by reversed-phase thin-layer chromatography using binary dioxane-water mobile phase. Chelate ligands were prepared by condensation of diamine and the corresponding beta-diketone. Copper(II) and nickel(II) complexes with chelate ligands containing ethane-1,2-diamine or propane-1,2-diamine as the amine part and pentane-2,4-dione and/or 1-phenylbutane-1,3-dione, pentane-2,4-dione and/or 1,1,1-trifluoropentane-2,4-dione, or 1,1,1-trifluoropentane-2,4-dione and/or 1-phenylbutane-1,3-dione as the beta-diketone part were synthesized. Some of investigated compounds were screened for their in vitro antifungal activity against Sacharomyces cerevisiae and antibacterial activity against Escherichia coli. Chromatographically obtained lipophilicity parameters were correlated both with calculated n-octanol-water partition coefficient C log P and antimicrobial activities. Satisfactory correlations were obtained. Chromatographic data proved to be reliable parameters for describing the lipophilic properties of the investigated compounds. Additionally, the principal components analysis was performed on the data chromatographically obtained. This statistical method was useful for distinguishing compounds and objective comparison of their lipophilicity parameters.     

New 7-substituted quinolone antibacterial agents. II. The synthesis of 1-ethyl-1,4-dihydro-4-oxo-7-(pyrazolyl,isoxazolyl, and pyrimidinyl)-1,8-naphthyridine and quinolone-3-carboxylic acids

Synthetic methods for the construction of certain aromatic heterocyclic side chains for the quinolone anti-bacterials have been provided. In particular a series of 7-(pyrazol-3 or 4-yl, 4- or 5-isoxazolyl and 4- or 5-pyrimidinyl)-1-ethyl-1,4-dihydro-4-oxo-1,8-naphthyridine and quinoline-3-carboxylic acids have been prepared. All of the heterocycles were prepared from masked 1,3-dicarbonyl derivatives of nalidixic acid ( 9,17 ) or 7-acetyl-1-ethyl-1,4-dihydro-4-oxo-3-quinoline carboxylic acids ( 8 ). These masked 1,3-dicarbonyl derivatives were prepared by the use of t-butoxy-bis-dimethylaminomethane on the activated methyls of 9,19 and 8 . The pyrimidinyl analogs, substituted with a 2-amino or a 2-aminomethyl moiety, were the only derivatives with substantial antibacterial activity.     

Studies on anti-ulcer agents. II. Synthesis and anti-ulcer activities of 6-isopropylazulene-1-sodium sulfonate derivatives

A series of alkylazulene-1-sodium sulfonate derivatives which has an isopropyl group at 6-position were synthesized, and their anti-ulcer activities were examined in Shay pylorus-ligated rats. The values of lipophilicity (log P) as a parameter of these new azulene derivatives were also examined in reference to the structure-activity relationship. The optimum value of log P, which showed maximal anti-ulcer activity, was about -0.46. Among the derivatives of azulene examined, 3-ethyl-6-isopropylazulene-1-sodium sulfonate (compound IXb:XT1-785) exhibited the most potent inhibitory action against Shay ulcer, and its anti-peptic activity was similar to that of 3-ethyl-7-isopropylazulene-1-sodium sulfonate (KT1-32). It also had more activity than guaiazulene sodium sulfonate (GAS). Furthermore, KT1-785 was extremely stable under heating as compared to GAS.     

Synthesis,antioxidant, and antimicrobial activity of 3-(1H-indole-3-carbonyl)-2H-chromen-2-ones

A simple and convenient method for the one-pot synthesis of 3-(1H-indole-3-carbonyl)-2H-chromen-2-one derivatives from the reaction of 3-cyanoacetyl indole and salicylaldehyde in the presence of Na₂CO₃ in water: methanol (1:1) is described. Wider substrate scope, high yields, operational simplicity, and simple purification process make the protocol highly applicable in the synthesis of 3-(1H-indole-3-carbonyl)-2H-chromen-2-ones. For the first time, in vitro antioxidant and antimicrobial activity was studied. Compounds 5e , 7a , and 7b exhibits good radical scavenging ability against DPPH free radical. Compounds 7b , 5f , and 5g possess lower EC₅₀ values than the Standards AA and BHA and thus proving their high reducing power. Compounds 5d and 5f show good antibacterial activity against gram-positive bacteria (MRSA) while compounds 5c , 7a , and 7b exhibits good antibacterial activity against Bacillus sp. Compounds 5b and 5e show good antibacterial activity against gram negative bacterial strains (Escherichia coli, Klebsiella pneumoniae) and compounds 5g and 5h exhibits good antifungal activity against Candida albicans.     

Fragmentation study of salinomycin and monensin A antibiotics using electrospray quadrupole time-of-flight mass spectrometry

The fragmentation pathways of two selected ionophore antibiotics, salinomycin and monensin A, were studied using electrospray (ES) orthogonal acceleration quadrupole time-of-flight mass spectrometry in positive-ion mode. The identity of fragment ions was determined by accurate-mass measurements. In ES mass spectra, ion signals of relatively high intensity were observed for [M+Na](+) and [M-H+2Na](+) for each antibiotic. Each of the ion species [M+Na](+) and [M-H+2Na](+) for salinomycin and [M-H+2Na](+) for monensin A were isolated in turn and subjected to fragmentation. In the fragmentation of [M+Na](+) and [M-H+2Na](+) from salinomycin, only Cbond;C single bond cleavage and dehydration were observed. Product ion mass spectra obtained from [M-H+2Na](+) of monensin A showed that ether ring opening, Cbond;C single bond cleavage and dehydration fragmentations had occurred. Fragment ions containing two sodium atoms were observed in the product ion mass spectrum of [M-H+2Na](+) from salinomycin, but not from monensin A. Both type A (containing the terminal carboxyl group) and type F (containing the terminal hydroxyl group) fragment ions were observed in the product ion mass spectra of sodium adduct ions of salinomycin and monensin A.     

Synthesis of Cu-TiNT,characterization, and antibacterial properties evaluation

Copper ion–exchanged titanate nanotubes (Cu-TiNTs) had been prepared from a simple ion-exchange reaction between copper salt and sodium titanate nanotubes (Na-TiNT) which was synthesized by alkaline hydrothermal synthesis starting from titanium oxide of anatase phase. A thorough structural and morphological characterization of Cu-TiNT (and Na-TiNT) was done by using various material characterization techniques, such as X-ray diffraction, Raman spectroscopy, energy-dispersive X-ray spectroscopy, and transmission electron microscopy to reveal retention of tubular structure of titanate nanotubes with decoration of copper (II) oxide on the surface of the tubes as well as an exchange of Na⁺ ion by Cu²⁺ ion in the interlamellar space. The antibacterial properties of the Cu-TiNT were evaluated by broth macrodilution method using microtiter trays, with concentration ranging between 512 and 0.5 μg/mL. The Cu-TiNT demonstrated no clinically relevant antibacterial activity alone (minimum inhibitory concentration ≥ 1024 μg/mL), but when associated with gentamicin, this compound enhanced the antibiotic activity of this drugs against strains of Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli. The results were very promising to the utilization of the Cu-TiNT as an adjuvant to the antibiotic therapy.     

两个7-氧杂-二苯芴-3，11-二磺酸镉化合物的合成、结构与荧光性质研究(英)

通过使用浓硫酸对2，2′-二羟基-1，1′-二萘的磺化与成环反应得到一种新配体，7-氧杂-二苯芴-3，11-二磺酸。通过水热方法得到了它的两个化合物，[CdL(bipy)₂(H₂O)][Cd(bipy)₂(H₂O)₂]·L·H₂O (1)和[CdL(phen)₂(H₂O)]·5H₂O (2)，并通过X-射线单晶衍射分析进行结构表征。化合物1以P1空间群结晶，晶胞参数为a=1.205 5(6)，b=1.576 4(8)，c=1.954 5(10) nm，α=75.755(9)，β=88.093(10)，γ=89.035(10)°。化合物2以P2₁/ c空间群结晶，晶胞参数为a=2.104 0(7)，b=1.358 0(4)，c=1.428 9(5) nm，β=94.543(6)°。在化合物1中，有两个独立的镉(Ⅱ)离子不对称单元，在其中镉(1)离子和两个联吡啶上的四个氮原子，磺酸配体上的一个氧原子及一个水分子配位；镉(2)离子和两个联吡啶上的四个氮原子和两个水分子配位。两种固体化合物在室温下均显示强的蓝色荧光。     

Synthesis and bioactivities of novel 2-(thioether/sulfone)-5-pyrazolyl-1,3,4-oxadiazole derivatives

By introducing the pyrazole moiety into the 5-position of 1,3,4-oxadiazole,a series of novel 2-(thioether/sulfone)-5-pyrazolyl-l,3,4-oxadiazole derivatives were synthesized.Preliminary bioassays suggested that target compounds exhibited appreciable activity against pathogenic bacteria Xanthomonas oryzae pv.oryzae(Xoo) and five phytopathogenic fungi in vitro.Among them,the half-maximal effective concentration(EC_(50)) values of 6c,7a,7b and 7c against Xoo were within 16.6 μg/mL and 65.7 μg/mL,which were better than those of commercial agricultural antibacterial bismerthiazol(92.6 μg/mL) and thiodiazole copper(121.8 μg/mL).While compounds 7a,7b,and 7c exerted comprehensive antifungal activity toward five plant fungi,which were comparable with that of hymexazol.The results demonstrated that this kind of compounds can be further studied and developed as promising antifungal and antibacterial agents.