1H and 13C NMR characterization of hemiamidal isoniazid-NAD(H) adducts as possible inhibitors of InhA reductase of Mycobacterium tuberculosis

Isoniazid (INH) is easily oxidized with manganese(III) pyrophosphate, a chemical model of the KatG protein involved in activation of INH inside the bacteria Mycobacterium tuberculosis. Performed in the presence of NAD(+), this oxidation generates a family of isomeric INH-NAD(H) adducts, which have been shown to be effective inhibitors of InhA, an enzyme essential in mycolic acid biosynthesis. In this work, we fully characterized by (1)H and (13)C NMR spectroscopy four main species of INH-NAD(H) adducts that coexist in solution. Two of them are open diastereoisomers consisting of the covalent attachment of the isonicotinoyl radical at position four of the nicotinamide coenzyme. The other two result from a cyclization involving the amide group from the nicotinamide and the carbonyl group from the isonicotinoyl radical to give diastereoisomeric hemiamidals. Although an INH-NAD(H) adduct with a 4S configuration has been characterized within the active site of InhA from Xray crystallography and this bound adduct interpreted as an open form (Rozwarski et al., Science 1998, 279, 98-102), it is legitimate to raise the question about the effective active form(s), open or cyclic, of INH-NAD(H) adduct(s). Is there a single active form or are several forms able to inhibit the InhA activity with different levels of inhibitory potency?     

Formulation and Optimization of Alkaline Extracted Ispaghula Husk Microscopic Reservoirs of Isoniazid by Box-Behnken Statistical Design

The main objective of the present work was to formulate and optimize a microparticulate sustained release drug delivery system of isoniazid by using a novel, alkaline extracted ispaghula husk as a polymer. Isoniazid microspheres of alkaline extracted ispaghula husk were prepared by emulsification internal ionic gelation method. Results of preliminary trials indicated that the polymer concentration, cross-linking agent and stirring speed had a noticeable effect on size and surface morphology. A four-factor three-level Box-Behnken design was employed to study the effect of independent variables on dependent variables. The particle size and entrapment efficiency varied from 30.75 to 61.78 µm and 62.27% to 85.80% respectively, depending on the polymer concentration, concentration of cross-linker and stirring speed. Optimized microspheres batch based on point prediction tool of design software exhibited 83.43% drug entrapment and 51.53 µm particle size with 97.80% and 96.37% validity, respectively at the following conditions: sodium alginate (3.55% w/v), alkaline extracted ispaghula husk (3.60% w/v), cross-linker concentration (7.82% w/v), and stirring speed (1200 rpm). The optimized formulation showed controlled drug release for more than 12 hours. The drug release followed Higuchi kinetics via a non-Fickian diffusion.     

Cinnamic acid hydrogen bonds to isoniazid and N′‐(propan‐2‐ylidene)isonicotinohydrazide,an in situ reaction product of isoniazid and acetone

A new polymorph of the cinnamic acid–isoniazid cocrystal has been prepared by slow evaporation, namely cinnamic acid–pyridine‐4‐carbohydrazide (1/1), C₉H₈O₂·C₆H₇N₃O. The crystal structure is characterized by a hydrogen‐bonded tetrameric arrangement of two molecules of isoniazid and two of cinnamic acid. Possible modification of the hydrogen bonding was investigated by changing the hydrazide group of isoniazid via an in situ reaction with acetone and cocrystallization with cinnamic acid. In the structure of cinnamic acid–N′‐(propan‐2‐ylidene)isonicotinohydrazide (1/1), C₉H₈O₂·C₉H₁₁N₃O, carboxylic acid–pyridine O—H...N and hydrazide–hydrazide N—H...O hydrogen bonds are formed.     

纳米金催化Luminol-H_2O_2化学发光体系对异烟肼的测定

碱性条件下,纳米金对Luminol-H2O2化学发光体系有增敏作用,而异烟肼对该化学反应具有强烈的抑制作用。基于此,在优化化学发光反应条件的基础上,提出了一种测定异烟肼的新方法,并对其可能的化学发光机理进行了探讨。该方法测定异烟肼的线性范围为0.005~9.0 mg/L,检出限(3σ)为3.0μg/L,相对标准偏差为3.5%(n=11,ρ=0.2 mg/L)。该法已成功用于药物制剂中异烟肼含量的测定。     

多壁碳纳米管-酰基吡唑啉酮复合膜修饰电极测定异烟肼

报道了一种修饰电极--多壁碳纳米管-酰基吡唑啉酮复合膜修饰玻碳电极(MWNTs/HPMαFP/GCE ),研究了异烟肼在此修饰电极上的电化学行为及反应机理.与裸GCE和MWNTs/GCE相比,异烟肼在MWNTs/HPMαFP/GCE上的氧化峰电流和检测灵敏度大大提高,表明多壁碳纳米管和酰基吡唑啉酮产生了协同增效作用.在...     

Enhanced Electrochemical Response of Isoniazid Electrocatalytic Oxidation on RGO-PPD-SiW Modified Electrode

The electroactive composites based on reduced graphene oxide (RGO), poly-o-phenylenediamine (PPD) and heteropolyacids – H₄SiW₁₂O₄₀nH₂O (SiW) and H₃[PW₁₂O₄₀] ⋅ nH₂O (PW) was applied to a screen-printed carbon electrode (SPCE) as a planar three-electrode cell as the first step to creating various devices, in particular, sensors and catalysts. We studied potential use of the modified and unmodified SPCE planar electrode in determining the concentration of antitubercular antibiotic isoniazid (isonicotinic acid hydrazide C₆H₇N₃O or INH). The best result was observed for SPCE+RGO-PPD-SiW. CV of normal saline with various concentrations of C₆H₇N₃O demonstrated linear dependence of the relevant anodic peak current either in the bulk solution upon immersion of the modified electrode or in a droplet on the electrode surface.     

金纳米粒子催化鲁米诺-异烟肼化学发光反应及其分析应用

研究发现, 在金纳米粒子存在下, 异烟肼与鲁米诺反应可产生强的化学发光. 采用响应曲面优化法中的Box-Behnken设计, 对试剂浓度进行了优化. 在优化的实验条件下, 相对化学发光强度与异烟肼的质量浓度在5.0× 10^－9～3.0×10^－7 g/mL范围内呈线性关系. 方法的检出限为4.1×10^－9 g/mL异烟肼, 相对标准偏差为1.3% (1.0×10^－7 g/mL异烟肼溶液, n＝11). 该方法已用于片剂、注射液和人血清中异烟肼含量的测定. 同时, 对化学发光反应的可能机理也进行了讨论.     

Highly Sensitive Electrogenerated Chemiluminescence Isoniazid with NiO Nanoparticles‐modified Graphite Electrode

Abstract

NiO nanoparticles (NiO NPs) were prepared with chemical precipitation method and modified on the surface of vaseline‐impregnated graphite electrode with chitosan. It was found that, based on the catalysis of the NiO NPs for the chemiluminescent reaction of the ECL process, the enhancing effect of isoniazid on the weak electrogenerated chemiluminescence (ECL) signal of luminol at a NiO NPs‐chitosan modified electrode was stronger than that at a bare graphite electrode. Under the optimum experimental conditions, the relative ECL intensity was linear with isoniazid concentration over the range 3.0×10^?10～1.0×10^?6 g/ml at the NiO NPs‐chitosan modified electrode with a detection limit of 1.0×10^?10 g/ml.     

Flow Injection Chemiluminescence Determination of Isoniazid Using On-Line Electrogenerated Manganese(III) as Oxidant

A novel flow injection chemiluminescence (CL) system for the determination of isoniazid has been proposed. It is based on the direct CL reaction of isoniazid and Mn(III) in sulfuric acid medium. The unstable Mn(III) was on-line electrogenerated by constant current electrolysis. The CL emission intensity was linear with isoniazid concentration in the range 0.1–10 μg/mL; the detection limit was 3.2 × 10⁻² μg/mL. The whole process could be completed in 1 min with a relative standard deviation of less than 5%. The proposed method is suitable for automatic and continuous analysis and has been applied successfully to the analysis of isoniazid in pharmaceutical preparation.     

在线自发电源激发的流动注射电致化学发光测定异烟肼

采用了一种与流动注射体系组合的在线自发电池作为电致化学发光的激发源（ 简称FI－GCECL）。实验发现在碱性介质中，Al/Ag双金属对可以提供稳定的电位输 出并可激发鲁米诺在铂电极表面的电致化学发光。此自发电池具有使用寿命长、电 位可由碱性介质组成调节、可组合到流动注射体系中等特点，利用这种组合体系， 检测了三家厂生产的片剂中的异烟肼含量，将结果与药典标准方法进行了比较，证 明了这种电致发光分析的可行性。