Targeting alpha-synuclein in Parkinson's disease

alpha-Synuclein aggregation into fibrils is associated with the pathogenesis of Parkinson's disease (PD). Li et al. provide strong evidence that rifampicin interacts with alpha-synuclein and inhibits its fibrillization. Rifampicin could be a promising candidate for therapeutic application for PD.     

Thermal studies of isoniazid and mixtures with rifampicin

Rifampicin–Isoniazid mixture is a frequently used product in the treatment of tuberculosis. Rifampicin exhibits polymorphism and exists in two polymorphic forms: the stable form I and the metastable form II. The aim of this work was to evaluate the thermal behavior of the binary mixtures of polymorphs I and II of rifampicin and isoniazid by using DSC. Mixtures of different forms (rifampicin form I and II) showed interaction with isoniazid indicating that the mixtures are less stable compared to the drug alone. Interaction was observed in case of both polymorphs of rifampicin.     

Evaluation of the physico-chemical properties of chitosan as a potential carrier for rifampicin, using voltammetric and spectrophotometric techniques

Rifampicin is an antibiotic which, on a carbon paste electrode, shows an oxidation response of 0.492 V (vs. Ag/AgCl) at pH 7.0, due to the electroactivity of the hydroquinone group. Interaction of rifampicin with chitosan is strongly dependent on pH, species concentrations and contact time between the latter. Compared to the carbon paste electrode, electrodes modified with chitosan showed greater sensitivity, with optimum voltammetric profile obtained at pH 8.0. Spectrophotometric measurements indicate that rifampicin is strongly absorbed by chitosan at pH less than the pKa of the pharmaceutical, such behaviour being favourable for the use of chitosan as a carrier for the controlled release of rifampicin in the intestinal tract.     

Design,synthesis and in silico study of pyridine based 1,3,4-oxadiazole embedded hydrazinecarbothioamide derivatives as potent anti-tubercular agent

Development of novel, safe and effective drug candidates combating the emerging drug resistance has remained a major focus in the mainstream of anti-tuberculosis research. Here, we inspired to design and synthesize series of new pyridin-4-yl-1,3,4-oxadiazol-2-yl-thio-ethylidene-hydrazinecarbothioamide derivatives as potential anti-tubercular agents. The anti-tubercular bioactive assay demonstrated that the synthesized compounds exhibit potent anti-tubercular activity (MIC = 3.9–7.81 μg/mL) in comparison with reference drugs Rifampicin and Isoniazid.We employed pharmacophore probing approach for the identification of CYP51 as a possible drug target for the synthesized compounds. To understand the preferable binding mode, the synthesized molecules were docked onto the active site of Sterol 14 α-demethylases (CYP51) target. From the binding free energy of the docking results it was revealed that the compounds were effective CYP51 inhibitors and acts as antitubercular agent.     

5(4H)‐Oxazolones as Novel Antitubercular Agents: Synthesis,Characterisation and Structure Activity Study

In search of novel anti tubercular agents, a series of twelve 4‐(substituted benzylidene)‐2‐p‐tolyloxazol‐5(4H)‐ones (5a – 5l) has been synthesized, characterised and subjected to evaluate their antitubercular activity for the first time against Mycobacterium tuberculosis H37Rv (ATCC 27294). The out‐put of these studies disclosed that all the synthesized target molecules of the series displayed good to moderate activity with MIC values ranging 2–32 μg/mL in comparison with the standard first line antitubercular drugs Rifampicin and Isoniazid. Compound 5e with three methoxy groups meta to each other, is the most distinctive compound identified amongst the series, because of its remarkable in vitro antitubercular activity and thus may act as a promising lead molecule for further explorations.     

Rapid determination of rifaximin on dried blood spots by LC‐ESI‐MS

The use of blood spot collection cards is a simple way to obtain specimens for therapeutic drug monitoring, assessing adherence to medications and preventing toxicity in a clinical setting. A high‐throughput liquid chromatography–electrospray ionization mass spectrometric (LC‐ESI‐MS) method for determination of rifaximin on dried blood spots (DBS) was developed and validated. It involves solvent extraction of a punch of DBS followed by reversed‐phase LC on a monolithic column consisting of a silica rod with bimodal pore structure and detection by ESI‐MS. Rifampicin was used as an internal standard (IS). The run time was within 5.0 min with a very low back‐pressure at a flow rate of 0.5 mL/min. The assay was linear from 0.1 to 10 ng/mL. The mean recovery was 98.42%. The developed method is very simple, rapid and useful for clinical applications. Copyright © 2011 John Wiley & Sons, Ltd.     

Ameliorating effects of Tamarindus indica fruit extract on anti-tubercular drugs induced liver toxicity in rats

The study aimed to evaluate the hepatoprotective potential of aqueous extract of Tamarindus indica fruit against combination of two antitubercular drugs viz. Isoniazid and Rifampicin induced hepatotoxicity in rats. In vitro antioxidant activity of aqueous extract of T. indica by DPPH–HPLC method was found to be 81.48%. Treatment with aqueous extract of T. indica significantly reduced the elevated levels of biochemical markers such as SGOT, SGPT, ALP, bilirubin, TBARS and increased the albumin level as well antioxidant activities of SOD, CAT and GSH in intoxicated rats. The biochemical changes were supported by histological observations. Results of this study clearly demonstrate that aqueous extract of T. indica fruit protects against anti tuberculosis induced oxidative liver damage in rats and thus possess significant hepatoprotective activity. Further, it could be suggested that supplementation with this food extract might prove beneficial in the individuals on anti-TB drugs.     

Redetermination of rifampicin pentahydrate revealing a zwitterionic form of the antibiotic

Rifampicin belongs to the family of naphthalenic ansamycin antibiotics. The first crystal structure of rifampicin in the form of the pentahydrate was reported in 1975 [Gadret, Goursolle, Leger & Colleter (1975). Acta Cryst. B 31 , 1454–1462] with the rifampicin molecule assumed to be neutral. Redetermination of this crystal structure now shows that one of the phenol –OH groups is deprotonated, with the proton transferred to a piperazine N atom, confirming earlier spectroscopic results that indicated a zwitterionic form for the molecule, namely (2S,12Z,14E,16S,17S,18R,19R,20R,21S,22R,23S,24E)‐21‐acetyloxy‐6,9,17,19‐tetrahydroxy‐23‐methoxy‐2,4,12,16,18,20,22‐heptamethyl‐8‐[(E)‐N‐(4‐methylpiperazin‐4‐ium‐1‐yl)formimidoyl]‐1,11‐dioxo‐1,2‐dihydro‐2,7‐(epoxypentadeca[1,11,13]trienimino)naphtho[2,1‐b]furan‐5‐olate pentahydrate, C₄₃H₅₈N₄O₁₂·5H₂O. The molecular structure of this antibiotic is stabilized by a system of four intramolecular O—H...O and N—H...N hydrogen bonds. Four of the symmetry‐independent water molecules are arranged via hydrogen bonds into helical chains extending along [100], whereas the fifth water molecule forms only one hydrogen bond, to the amide group O atom. The rifampicin molecules interact via O—H...O hydrogen bonds, generating chains along [001]. Rifampicin pentahydrate is isostructural with recently reported rifampicin trihydrate methanol disolvate.     

利福霉素类抗生素-Cu(II)-核酸体系的RRS光谱研究

在Britton-Robinson (B-R)缓冲溶液中, 利福霉素类药物与ctDNA反应的适宜的pH范围是1.9～2.1. 此类药物本身有微弱RRS峰, 它们具有相似的光谱特征, 其散射峰均在290和370 nm附近; 而ctDNA的RRS峰在310 nm处. 两者反应形成结合产物后其RRS明显增强, 并在375 nm左右出现最大散射峰, 且有不同程度的红移和散射增强, 说明两者结合成新的产物; 加入Cu2＋离子后, Cu2＋与利福霉素抗生素及DNA形成三元复合物, 此时将导致RRS进一步剧增, 而且RRS光谱增强值与DNA浓度呈正比, 因而可用于DNA测定具有较高的灵敏度, 实验对ctDNA的检出限为9.7 ng/mL (RFSV-Cu2＋- ctDNA体系). 文中研究了三元配合物反应的适宜条件和影响因素, 基于此反应发展了一种用RRS技术测定DNA的新方法.     

Simultaneous determination of rifampicin and sulbactam in mouse plasma by high-performance liquid chromatography

A simple and rapid high-performance liquid chromatographic (HPLC) method with ultraviolet detection has been developed and validated for the simultaneous determination of rifampicin and sulbactam in mouse plasma. Plasma samples were deproteinized with acetonitrile and separated by HPLC on a RP-18 (125 x 4 mm, 5 microm) column and gradient elution with potassium dihydrogen phosphate solution (pH 4.5; 50 mm) and acetonitrile at a flow-rate of 1.0 mL/min. Rifampicin and sulbactam were monitored at 230 nm and confirmed by means of their UV spectra using a diode-array detector. The method was linear at plasma levels from 1 to 100 microg/mL for rifampicin and from 5 to 200 microg/mL for sulbactam. The limits of quantification were 0.6 microg/mL for rifampicin and 4.2 microg/mL for sulbactam. The intra- and inter-day precisions of the method (RSD) were lower than 5% for both compounds. Average recoveries of rifampicin and sulbactam from mice plasma were 98.2 and 89.3%, respectively. The developed method was successfully applied to the determination of the pharmacokinetic profile of both compounds in mice.     

Chitosan-polyvinyl alcohol membranes with improved antibacterial properties contained Calotropis procera extract as a robust wound healing agent

Due to excessive use of antibiotics, resistance against microorganisms is developed. An alternative use of antibiotics, natural remedies from plants have been used against infectious diseases. In the current study, bioactive compounds from Calotropis procera (C. procera) root were extracted and chitosan and polyvinyl alcohol (CS-PVA) were used asa carriers and for the delivery to treat induced infection. Different concentration of C. procera extracts (25–75 mg/mL) were loaded on CS-PVA membrane and applied on the induced wounds in rabbits. Wound reduction was recorded for 12 days. On 6th day, small tissue from healing area were collected and subject to histopathology for tissue regeneration. The antioxidant activity (DPPH, TPC and TFC) was also investigated of CS-PVA loaded C. procera root extract. The DPPH free radical inhibition for 75 mg/mL were recorded up to 66.37%. The TPC and TFC contents were recorded to be 36.52 ± 5.12 GAE mg/g of DW (dry weight) and 24.49 ± 6.27 CE mg/g of DW (dry weight), respectively. The antibacterial activity was evaluated against Escherichia coli and Staphylococcus aureus in comparison to control (Rifampicin). The zones of inhibition were recorded to be 18.50 ± 2.30 and 20.40 ± 4.20, respectively for CS-PVA membrane loaded with 75 mg extracts along with Rifampicin 28.50 ± 2.5 and 30.50 ± 1.38. The CS-PVA membranes were also studied for swelling and biodegradability. The biodegradability was increased, while swelling was decreased of CS-PVA membranes loaded with extract. The bioactive compounds from the CS-PVA loaded with extract released in controlled and sustainable way. Result revealed that CS-PVA loaded C. procera root extract has promising antimicrobial and antioxidant activity and could possibly be employed for the treatment of infectious diseases.     

Antitubercular Activity and Synergistic Study of Novel Pyrazole Derivatives

A series of 20 novel pyrazole derivatives were designed and prepared, characterized by ¹H‐NMR, mass spectra (ES‐MS), ¹³C‐NMR, and elemental analysis. The synthesized compounds were then evaluated for their growth inhibitory activity against Mycobacterium smegmatis mc² 155 initially. Rifampicin was used as standard reference. In this screening, derivatives 9 , 10 , and 11 presented superior inhibition compared with standard. Later, these three compounds were exposed for their Mycobacterium tuberculosis H37Rv inhibitory assay using rifampicin as standard reference. Encouraging M. smegmatis mc² 155 inhibition (9 μg/mL), M. tuberculosis H37Rv inhibition (1.9 μg/mL), and synergism with the first‐line and second‐line antibiotics made compound 10 as lead and safe antitubercular agent among the series.     

Spectrophotometric determination of rifampicin through chelate formation and charge transfer complexation in pharmaceutical preparation and biological fluids

Two simple and accurate spectrophotometric methods for determination of Rifampicin (RIF) are described. The first method is based on charge transfer (CT) complex formation of the drug with three pi-electron acceptors either 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), 7,7,7,8-Tetracyanoquinodimethane (TCNQ) or 2,3,5,6-Tetrachloro-1,4-benzoquinone (p-chloranil) in acetonitrile. The method is followed spectrophotometrically by measuring the maximum absorbance at 584 nm, 761 nm (680 nm) or 560 nm for DDQ, TCNQ and p-chloranil, respectively. Under the optimized experimental conditions, the calibration curves showed a linear relationship over the concentration ranges of 5-140 microg/ml, 2-45 microg/ml (5-120 microg/ml) and 15-200 microg/ml, respectively. The second method is based on the reaction of RIF with iron(III) forming a water insoluble violet complex which is extracted into chloroform. The method determines RIF in concentration range of 10-240 microg/ml at 540 nm. The proposed methods applied to determination of RIF in capsule, human serum and urine samples with good accuracy and precision. The results were compared statistically with the official method and showed no significant different between the methods compared in terms of accuracy and precision.     

Determination of Rifampicin by Peroxomonosulfate‐Cobalt(II) Chemiluminescence System

Rifampicin can enhance the chemiluminescence (CL) of peroxomonosulfate‐cobalt(II) system, and the CL intensity is strongly dependent on the rifampicin concentrations. Based on this phenomenon, a rapid and sensitive flow injection CL method was developed for the determination of rifampicin. The relative CL intensity was linear with the rifampicin concentration over the range of 5×10^?8 to 1×10^?6 g·mL^?1 (r=0.9991), the detection limit was 7×10^?9 g·mL^?1 (S/N=3), and the relative standard deviation was 2.7% for 6×10^?7 g·mL^?1 rifampicin (n=11). Furthermore, this method was successfully applied to the determination of rifampicin in real eye drop and capsules sample.     

Polyvinylpyrrolidone–polycaprolactone block copolymer micelles as nanocarriers of anti-TB drugs

A range of polyvinylpyrrolidone–polycaprolactone diblock copolymers with varying chain lengths were synthesized by Atom Transfer Radical Polymerisation (ATRP) using bromo-polycaprolactone as macroinitiator and copper(I) bromide/bipyridine catalytic system. The copolymers self-assembled in solution into core–shell micelles with sizes varying from 150 to 205 nm and critical micelle concentration of the order of 10⁻⁵ to 10⁻⁶ M. Front line anti-Tuberculosis drugs Rifampicin (RIF), Pyrazinamide (PZA) and Isoniazid (INH) were successfully encapsulated within the micelle hydrophobic core singly or in dual combination. The effect of length of hydrophobic and hydrophilic segments on drug loading, micelle size and drug release was investigated. Determination of binding constants showed that RIF binds more strongly to the micelle core than PZA and INH, leading to highest drug loading content. All drugs were released in vitro (PBS solution at 37 °C) in a sustained manner with zero-order kinetics and followed the order INH > PZA > RIF.     

Quantitative determination of rifampicin in aquatic products by stable isotope-dilution high liquid chromatography–tandem mass spectrometry

Rifampicin is a semi-synthetic broad-spectrum antibiotic obtained from rifamycin B. It is one of the most effective first-line antituberculosis drugs and is widely used in clinical practice. In the present study, we describe a rapid and sensitive method for the determination of rifampin in aquatic products by stable isotope-dilution high liquid chromatography–tandem mass spectrometry (HPLC–MS/MS). Samples were extracted with the acetonitrile, degreased by hexane, and then concentrated by nitrogen blowing. After separation using a C₁₈ column with a mixture of acetonitrile and water as mobile phase, it was determined by HPLC–MS/MS using the stable isotope-dilution calibration method. The performance of our method was validated. The limit of detection was 0.25 μg kg⁻¹ and the limit of quantification was 0.5 μg kg⁻¹. At the three spiked levels of 0.5, 1.0 and 5.0 μg kg⁻¹, the average recoveries of rifampicin in different aquatic products were between 75.28 and 107.6%, and the relative standard deviation ranged from 0.81 to 13.23%. This method was successfully applied for the determination of rifampin in different kinds of aquatic products and rifampicin residue was found in aquatic products obtained from markets in Beijing, China.     

An iboga alkaloid chemotaxonomic marker from endemic Tabernaemontana ternifolia with antitubercular activity

Abstract

Coronaridine (1) was isolated from the CH₂Cl₂ root extract of Tabernaemontana ternifolia. The structure of 1 was established from 1D- and 2D-NMR and HR-ESIMS experiments, and by comparison with reported spectroscopic data. To date, this is the first report of compound 1 from T. ternifolia, introduced as new Tabernaemontana species from Philippines in 2005 on the basis of morphological characters. Coronaridine, an iboga-type indole alkaloid, has been isolated from over 50 Tabernaemontana species and can thus be inferred as a chemotaxonomic marker of the genus. T. ternifolia has a distinct arrangement of leaves not known in the genus, but is variable in other genera. Its isolation from endemic T. ternifolia establishes its position in the genus and supports the claim that coronaridine is a chemical marker of the genus Tabernaemontana. Interestingly, coronaridine exhibited relatively weak activity against Mycobacterium tuberculosis H₃₇Rv (MIC 82.64?μg/mL) (Rifampicin MIC 0.05?μg/mL).     

Electrochemiluminescence from successive electro- and chemo-oxidation of rifampicin and its application to the determination of rifampicin in pharmaceutical preparations and human urine

A novel electrochemiluminescence (ECL) type was proposed based on successive electro- and chemo-oxidation of oxidable analyte, which was different from both annihilation and coreactant ECL types in mechanism. Rifampicin was used as a model compound. No any chemiluminescence (CL) was produced by either electrochemical oxidation or chemical oxidation of rifampicin in KH(2)PO(4)--Na(2)B(4)O(7) (pH 6.6) buffer-dodecyl trimethyl ammonium chloride (DTAC) solution. However, an ECL was observed by electrochemical oxidization of rifampicin in the same solution in the presence of oxidant such as dissolved oxygen, activated oxygen and potassium peroxydisulfate (K(2)S(2)O(8)). The ECL was attributed to electrochemical oxidation of rifampicin to form semiquinone free radical, and then subsequently chemical oxidation of the formed radical by oxidant to form excited state rifampicin quinone. The proposed ECL type introduced additional advantages such as high selectivity, simple and convenient operation, and effective avoidance of side reaction that often took place in homogenous CL reaction, and will open a novel application field. In addition, with the ECL in the presence of K(2)S(2)O(8) as oxidant, a flow injection ECL method for the determination of rifampicin was proposed. The ECL intensity was linear with rifampicin concentration in the range of 1.0 x 10(-7) to 4.0 x 10(-5) mol l(-1) and the limit of detection (s/n=3) was 3.9 x 10(-8) mol l(-1). The proposed method was applied to the determination of rifampicin in pharmaceutical preparations and human urine.     

Dicationic liquid mediated synthesis of tetrazoloquinolinyl methoxy phenyl 4-thiazolidinones and their antibacterial and antitubercular evaluation

In a search of new potentially active antitubercular agents here we have synthesized 3-substituted phenyl-2-(4-(tetrazolo[1,5-a]quinolin-4-ylmethoxy)phenyl)thiazolidin-4-ones (8a–l) and evaluated their antibacterial, particularly antitubercular activity. These have been conveniently synthesized by performing one–pot cyclocondensation of 4-(tetrazolo[1,5-a]quinolin-4-ylmethoxy)benzaldehyde, anilines and mercaptoacetic acid in dicationic ionic liquid, (3-methyl-1-[3-(methyl-1H-imidazolium-1-yl)propyl]-1H-imidazolium dibromide [C₃(MIM)₂–2Br]) and obtained excellent yields of (8a–l). 4-Thiazolidinones (8a–l) were thoroughly characterized by their spectral analyses. These compounds have been screened for their in vitro antitubercular activity against Mycobacterium tuberculosis H37Ra and Mycobacterium bovis (BCG). The compounds 8a, 8c, and 8e exhibited notable in vitro antitubercular activity compare to the reference, Rifampicin. Molecular docking study has also been performed to know the binding mode of these analogs in to the active site of DprE1 enzyme. The synthesized compounds were also evaluated for their in vitro antibacterial activity and amongst them compound 8k has shown moderate activity against both gram-negative and gram-positive bacterial strains.     

柱吸附容量对蔗糖还原糖色谱分离过程产率和回收率的影响

本文采用了能反映流体轴向扩散的大型液相色谱分离过程数学模型,应用计算机模拟分析蔗糖和还原糖的色谱分离过程,从吸附剂吸附容量和柱装填密度两个方面;考察柱吸附容量对大型色谱分离的产率和回收率的影响。研究结果表明：在色谱柱中流体线速度恒定的条件下对多组分分离,回收率是随吸附剂吸附容量以及床层装填密度的增大而增大的;产率先随吸附剂吸附容量的增大而增大,而在出现峰值后下降;随着床层装填密度的增大,产率增加,但与此同时轴向扩散系数也增大,从而降低分离效率,导致在较高装填密度的范围内产率增力。的幅度减少。在相同的吸附剂用量下,采用短柱高装填密度的色谱柱将比长柱低装填密度色谱柱能获得更高的回收率和产率。