Versatile and facile synthesis of diverse semisynthetic tetracycline derivatives via Pd-catalyzed reactions

A diverse collection of tetracycline derivatives has been synthesized utilizing Heck, Suzuki, and other palladium-coupling reactions via tetracycline arenediazonium and iodoarene salts. Large numbers of tetracyclines are now possible via these reactions, including numerous upper periphery derivatives of doxycycline, minocycline, sancycline, and methacycline modified at positions C7, C9, and C6-C13 on the tetracycline naphthacene ring. Application of palladium-coupling reactions to the tetracyclines has yielded new tetracycline classes with differing structural attributes, greatly increasing the structural diversity of this family of antibiotics, one of the last of the early antibiotic families to be expanded by organic and medicinal chemistry.     

Palladium catalyzed C-N bond formation in the synthesis of 7-amino-substituted tetracyclines

A facile synthesis of 7-alkylamino- and 7-cycloalkylaminotetracycline derivatives has been accomplished using an in situ generated aminostannane precursor. This procedure is advantageous in that it allows the concise synthesis of a number of unreported tetracycline derivatives that are cumbersome to prepare through traditional methods. These compounds are crucial to understanding structure activity relationships in the D-ring of tetracycline-type antibiotics and the acquired efflux resistance mechanism to this class of antibiotics.     

四环素族化合物荧光标记蛋白质的研究

本文报道将四环素族化合物标记牛血清白蛋白的方法，研究了其偶联物的荧光特性，结果表明四环素族化合物具有良好的荧光标记蛋白质的功能。     

Improved high-speed counter-current chromatograph with three multilayer coils connected in series. II. Separation of various biological samples with a semi-preparative column

The semipreparative capability of the newly developed high-speed counter-current chromatograph equipped with a set of three multilayer coils has been demonstrated in separations of a variety of biological samples including triterpenoic acids, indole auxins, bacitracin, flavonoids and tetracycline derivatives, each with a suitable two-phase solvent system. The sample quantities ranging from 50 to 500 mg were efficiently separated within a few hours. The separation of tetracycline derivatives was remarkably improved by adding ammonium acetate to the solvent system.     

Metal binding characteristics of tetracycline derivatives in DMSO solution

A previous study of the site of metal binding in tetracycline has been extended to several derivatives of tetracycline in an effort to determine which specific functional groups are involved in binding to metal ions in DMSO solution and to explore relationships between antibacterial activity and metal binding characteristics. Proton NMR experiments using paramagnetic and diamagnetic lanthanide series ions as binding site probes indicate that the ring A tricarbonylmethane group is the binding site for tetracycline, 5-hydroxytetracycline, 4-epitetracycline and tetracyclinemethiodide in DMSO. No. NMR evidence for metal binding is found for 4-dedimethylaminotetracycline. Binding to Mg²⁺ is also investigated by NMR for several of these compounds, and a discussion of conformational preferences of tetracycline derivatives in DMSO is presented.     

Fluorimetric determination of tetracyclines with the europium chelate of 1,10-phenanthroline in micellar solutions of anionic surfactants

The fluorescence of europium(III) in micellar solutions of surfactants sensitized by tetracycline derivatives was studied. It was found that the fluorescence intensity in the system Eu³⁺-tetracycline derivatives increases in the presence of 1,10-phenanthroline by a factor of 3–4. In micellar solutions of sodium dodecylbenzene sulfonate, the signal additionally enhances by a factor of 2.5. A procedure was developed for determining tetracycline and three its derivatives in blood plasma.Translated from Zhurnal Analiticheskoi Khimii, Vol. 60, No. 1, 2005, pp. 30–34.Original Russian Text Copyright © 2005 by Shtykov, Smirnova, Bylinkin, Zhemerichkin.     

High-Performance Liquid Chromatography of Derivatives Involved in the Terminal Steps of Tetracycline Biosynthesis in Streptomyces Aureofaciens

Abstract

A simple and reproducible method was developed for the analysis of tetracycline derivatives involved in the last two steps of tetracycline biosynthetic pathway in Streptomyces aureofaciens. The method is based on a gradient liquid chromatographic separation of the compounds using a microbore octadecyl silica column. Beside separation of a mixture of standards, the method was used for separation, detection and quantitation of dehydrotetracycline and tetracycline prepared enzymatically in vitro using anhydrotetracycline oxygenase and tetracycline dehydrogenase, respectively, isolated from S. aureofaciens. The method permits a simple and accurate characterization of kinetics of corresponding enzymatic activities.     

Synthesis of tetracyclic hydroxyquinones by cycloaddition reactions with dienols.

Cycloaddition of naphthazarin and derivatives to dienols, generated thermnally from benzocyclobuenol or by irradiation of 2-methylbenzaldehyde or 2-methylacetophenone, leads to tetracyclic systems related to those present in anthracycline and tetracycline antibiotics.     

Fluorescence optical fiber sensor for tetracycline

A new optical fiber sensor for monitoring tetracycline has been described, based on the fluorescence quenching of 1,4-bis(5,5'-dimethylbenzoxazole-1',3'-yl-2')benzene incorporated into a thin plasticized polymer film by tetracycline extracted from aqueous phase into film phase. The sensor is fully reversible and highly reproducible. Furthermore, the sensor exhibits a linear response to tetracycline in the range 6.98x10(-7)-8.73x10(-5) mol l(-1) with a detection limit of 1.06x10(-7) mol l(-1), and with the response time <30 s. The response is also selective to tetracycline, with some common pharmaceutical species, alkali and alkali-earth metal salts being highly discriminated, suggesting that the sensor can be used to monitor tetracycline in three pharmaceutical preparations. The recovery of tetracycline from commercial formulations is 95.3-98.3%.     

Organocatalyzed Synthesis and Antibacterial Activity of Novel Quinolino Annulated Analogues of Azepinones

Starting from dimedone, two methodologies for synthesizing novel quinolino annulated azepinones have been reported. The protocol involves azepinone synthesis by the action of a newly synthesized organocatalyst derived from the reaction of TCT and DMF on oxime derivatives ( 5 and 9 ), which were obtained by the reaction of acridine dione derivatives ( 4 and 8 ) with hydroxylamine hydrochloride. The derivatives 4 and 8 were obtained by the reaction of 1 with anthranilic acid 2 and isatoic anhydride 7 , respectively. The synthesis of all the compounds was confirmed initially by TLC followed by spectral analysis through IR, ¹H NMR, ¹³C NMR, mass spectrometry, and elemental analysis. The results that emanated on the evaluation of the antibacterial activity of azepinones against two Gram‐positive and two Gram‐negative test organisms using disc diffusion method have also been discussed. Compounds 6c , 6d , 6e , 10c , and 10e have been found to display better inhibitory activity than standard drugs streptomycin and tetracycline. The minimum inhibitory concentration and IC₅₀ values for the compounds under study as well as of standard drugs were calculated. The maximum inhibition by bacterial strains was observed at 150 μg/mL.     

Eu~(3+)荧光探针构建及对牛奶中盐酸四环素残留的测定

本文构建了Eu~(3+)-苯甲酸(BA)-邻菲啰啉(Phen)三元配合物体系荧光探针,建立了一种检测牛奶中盐酸四环素残留的新方法。对三元配合物体系进行优化,确定Eu~(3+)、BA、Phen的最佳浓度配比为1∶1.5∶2,最佳检测时间为20min。该方法检测盐酸四环素的线性范围为1.0×10~(-6)~5.0×10~(-5) mol/L,检测限为1.8×10~(-7) mol/L。利用该荧光探针对处理后的牛奶进行加标回收实验,其回收率范围为99.5%~108%,平均回收率为103.8%。实验证明该方法科学可行,对盐酸四环素具有较高的选择性。     

SCRF-DFT and NMR comparison of tetracycline and 5a,6-anhydrotetracycline in solution

A combination of structures, energies, and spectral data calculated using density functional theory (DFT) with experimental NMR data has been used to assign conformational equilibria for tetracycline and 5a,6-anhydrotetracycline in water at pH 1, 7, and 10 and in chloroform (5a,6-anhydrotetracycline) and methanol (tetracycline). The results suggest that tetracycline always prefers the extended conformation but that 5a,6-anhydrotetracycline exists in water as a mixture of the two conformers and in chloroform exclusively in the twisted conformation. The conformational equilibria are also shown to be pH dependent.     

Determination of Tetracycline by Microdroplet Hydrodynamic Adsorptive Voltammetry Using a Multiwalled Carbon Nanotube Paste Rotating Disk Electrode

A novel and simple method is proposed for the determination of tetracycline by adsorptive voltammetry in a droplet using a carbon nanotube paste rotating disk electrode (CNTP-RDE). An enhanced electrochemical oxidation response of tetracycline was observed in pH 8.2 supporting electrolyte by the addition of a long-chain cationic surfactant, such as benzyldimethyltetradecylammonium chloride (zephiramine). Under the optimized experimental conditions, the calibration curve was linear across a tetracycline concentration range from 1.0?×?10^?7 to 2.0?×?10^?6 M. The limit of detection and sensitivity were 4.0?×?10^?8 M and 0.9358?A M^?1, respectively. This method was successfully employed for the determination of tetracycline in milk samples.     

Rapid separation of tetracycline derivatives and their main degradation products by capillary zone electrophoresis.

A mixture of five tetracycline (TC) derivatives: minocycline (MC), demeclocycline (DMCTC), doxycycline (DC), and sancycline (SC), as well as each TC derivative from its main degradation product were separated by capillary zone electrophoresis (CZE). The influence of the pH and the concentration and nature of the background electrolyte (BGE) on the separations was investigated. Ethylenediaminetetraacetic acid (EDTA; 1 mM) was used as additive in a 25 mM phosphate buffer (pH 2.3) because this BGE enabled the rapid separation of the TC derivatives and of each TC derivative from its respective degradation product in less than 6 min. After optimization of the separation conditions, the analytical characteristics of the method were investigated. The parameters involved were linearity, precision (repeatability and reproducibility), and limits of detection (LODs). LODs obtained for the five TC derivatives studied were about 3 microg/mL. Finally, the CZE method developed was applied to study the stability of TC derivatives and to analyze the TC derivative content in three different pharmaceutical preparations.     

Tetracycline Removal by Activating Persulfate with Diatomite Loading of Fe and Ce

Persulfate (PS)-based oxidation technology is efficient in removing refractory organics from water. A novel diatomite (DIA) support Fe and Ce composite (Fe-Ce/DIA) was prepared for activating persulfate to degrade tetracycline in water. The Fe and Ce were uniformly loaded on DIA, and the total pore size of Fe-Ce/DIA was 6.99 × 10⁻² cm³/g, and the average pore size was 12.06 nm. Fe-Ce/DIA presented a good catalytic activity and 80% tetracycline was removed under the persulfate system. The Fe-Ce/DIA also had photocatalytic activity, and the corresponding tetracycline removal efficiency was 86% under UV irradiation. Fe-Ce/DIA exhibited less iron dissolution rate compared with Fe-DIA. The tetracycline degradation rate was enhanced when the temperature increased. The optimal tetracycline removal efficiency was obtained when the conditions were of persulfate 10 mM, Fe-Ce/DIA dosage 0.02 g/L, and tetracycline concentration 50 mg/L. In addition, Fe-Ce/DIA showed a wide pH application and good reusability and stability.     

Design,synthesis, characterization,and antimicrobial evaluation of some new pyridine and chromene derivatives containing Lidocaine analogue

In an attempt to find a new class of antimicrobial agents, a series 2-pyridinone and 2-iminochromene derivatives containing Lidocaine analogue were designed and synthesized. The 2-pyridinone derivatives (3), (4), and (6) were obtained through the cyclocondensation of 2-cyano-N-(2,6-dimethylphenyl)-acetamide (2) with 1,3-dicarbonyl compounds and/or ternary condensation of (2), aromatic aldehyde, and malononitrile. Also, a series of 2-iminochromene derivatives (7–9) were synthesized through the condensation reaction of cyanoacetamide derivative (2) with salicylaldehyde derivatives. The structure of the new compounds were confirmed based on elemental analysis and spectral data. These compounds were screened for their antibacterial and antifungal activity The minimal inhibitory concentration (MIC) (µg/mL) of the most active (4), (5b), and (8) derivatives were determined. The MIC values between 7.81 and 31.26 µg/mL against bacterial species for (8) derivative, and upon comparison to tetracycline exhibited a positive control MIC (31.26–62.6 µg/mL). Besides, the activity against C. albicans (ATCC 1023) showed a MIC value of 15.63 µg/mL, which is similar to that of Amphotericin B.     

Improved High-Speed Countercurrent Chromatograph with Three Multilayer Coils Connected in Series. III. Evaluation of Semianalytical Column with Various Biological Samples and Inorganic Elements

Abstract

The partition efficiency of the counter-current chromatographic centrifuge was improved by mounting a set of three multilayer coils prepared from a 1.07 mm I.D. and ca 300 m length of PTFE (polytetrafluoroethylene) tube with a total capacity of 270 ml. The high performance of the present apparatus has been successfully demonstrated in separations of various testing samples which include DNP (dinitrophenyl) amino acids, indole auxins, tetracycline derivatives, flavonoids, bacitracin, triterpenoic acids, and lanthanoid chlorides.     

Flow-injection chemiluminescence determination of tetracyclines with in situ electrogenerated bromine as the oxidant

By designing a novel flow-through electrolytic cell (FEC), bromine was produced near to the surface of the platinum electrode by electrochemical oxidation of acidic KBr. The fast and weak chemiluminescence signal produced by the chemical reaction of the electrogenerated bromine with H₂O₂ was greatly enhanced by tetracyclines Based on these observations, a new, sensitive and simple electrogenerated chemiluminescence (ECL) method for the determination of tetracyclines was developed. Under the optimum experimental conditions, the calibration graphs are linear over the range 3.0×10⁻⁸ to 5.0×10⁻⁵ g ml⁻¹ for tetracycline, 2.0×10⁻⁷ to 2.4×10⁻⁵ g ml⁻¹ for oxytetracycline and 1.0×10⁻⁷ to 5.0×10⁻⁵ g ml⁻¹ for chlortetracycline. The limits of detection (S/N=3) are 1.0×10⁻⁸ g ml⁻¹ for tetracycline, 7.0×10⁻⁸ g ml⁻¹ for oxytetracycline and 1.5×10⁻⁷ g ml⁻¹ for chlortetracycline. For the determination 5.0×10⁻⁷ g ml⁻¹ tetracycline, the relative standard deviation was <5%. The proposed method was used to determine tetracyclines in pharmaceutical formulations.     

Kinetic Method of Tetracycline and Oxytetracycline Assay Using Spect-Rophotometric Measurements

Abstract

A Kinetic method is based on the degradation rate of tetracycline (TC) or oxytetracycline (OTC) to their anhydro derivatives with subsequent spectrophotometric measurements. With optimized degradation rate parameters, calibration curves relating decrease in absorbance difference (of alkaline solution versus acid solution) as a funotion of concentration in a range of 0.8-4.0 mg% are linear with negligible interecept. The method is applicable for powder and capsule assays and gives results within the pharmacopoeial limits.     

Ultrasensitive high‐performance liquid chromatography determination of tetracycline antibiotics and their 4‐epimer derivatives based on dual effect of methanesulfonic acid

In reversed‐phase liquid chromatography, tetracycline antibiotics yield broad and asymmetrical peaks, as a result of their ionic interaction with the anionic free silanol groups and metal ion present in the silica‐based stationary phases (commonly derivatized with C18 groups). These frequently encountered difficulties were absolutely eliminated based on dual effect when methanesulfonic acid was employed as an eluent additive. The study revealed that the performance of methanesulfonic acid to minimize the “silanol effect” is mainly explained by both direct neutralization of the anionic silanol sites and electrostatic attraction with analytes. Based on these dual action mechanisms, an ultrasensitive method has been successfully developed for the simultaneous determination of tetracycline antibiotics and their derivatives (minocycline, oxytetracycline, tetracycline, chlortetracycline, metacycline, doxycycline, 4‐epitetracycline, and 4‐epichlortetracycline) in bovine milk with convenient ultraviolet detection within 15 min. Under the optimal conditions, the calibration curves showed good linearity (r² > 0.999) for all analytes in the range of 1～200 ng/mL with the instrument limits of detection as low as 0.3 ng/mL. The study sheds new light on suitable additives to analyze basic compounds with the advantage of good compatibility with MS detection.