Farmaco (Societa chimica italiana : 1989)最新文献

Metrian [3-mercapto-5-(2′-hydroxynaphtylazo-1′)-1,2,4-triazole]; Metriap [3-mercapto-5-(3′,4′-dihydroxyphenylazo-1′)-1,2,4-triazole]; Metriarez-γ [3-mercapto-5-(2′,4′-dihydroxy-3′-caroboxyphenylazo-1′)-1,2,4-triazole] and Metidarez-β [2-mercapto-5-(2′,4′-dihydroxy-5′-carboxyphenylazo-1′)-1,3,4-thiadiazole]-reagents were synthesized on Faculty of Pharmacy, Medical University of Lublin and used for the determination by different analytical methods of milligram quantities of Fe(II) and Zn(II) occurring together in pharmaceutical preparations, both multivitamin preparations and those containing microelements. The determination results of classical spectrophotometry (D₀), spectrophotometry of derivatives (D₁ and D₂), atomic absorption spectrometric (AAS) and ions chromatography (IC) were analyzed statistically and compared with declared amount. The advantages of the proposed method of Fe(II) and Zn(II) determination include it's excellent precision and reproducibility of results.

Partial least-squares (PLS) calibration and principal component regression (PCR) methods were utilized for the simultaneous spectrofluorimetric and spectrophotometric determination of pyridoxine (PY) and melatonin (MT). Since emission and adsorption spectra of these drugs overlap, PY and MT cannot be directly determined by fluorimetric nor by spectrophotometric methods. Full-spectrum multivariate calibration PLS and PCR methods were developed for both fluorimetry and spectrophotometry. The conditions were optimized for fluorimetric as well as for spectrophotometric determination of both drugs. The simultaneous determination of PY and MT was carried out in mixtures by recording the emission fluorescence spectrum between 324 and 500 nm (λ_ex 285 nm) for fluorimetry, and by recording the absorption spectrum between 250 and 350 nm for spectrophotometry (λ_max(PY) 310 nm, λ_max(MT) 278 nm). The experimental calibration matrixes were designed orthogonally. At the optimum conditions, dynamic ranges were 0.04–1.3 and 0.1–4 μg ml^–1 for fluorimetry and 1–22 and 1–24 μg ml^–1 for spectrophotometry for MT and PY, respectively. The calibration concentrations were prepared in the dynamic ranges. The parameters of the chemometrics procedure for the simultaneous determination of MT and PY were optimized, and the proposed methods were validated with prediction set. Finally the procedures were successfully applied to simultaneous spectrofluorimetric and spectrophotometric determination of PY and MT in synthetic mixtures and in a pharmaceutical formulation.

A series of 64 derivatives of substituted heterocyclic analogues of salicylanilides was synthesized. The compounds were evaluated for in vitro antimycobacterial activity against Mycobacterium tuberculosis, Mycobacterium avium and two strains of Mycobacterium kansasii. For the QSAR study, the combination of Free–Wilson approach with Hansch approach was used. The molecules were separated on the heterocyclic and salicyl moieties and the study of influences of electronic and hydrophobic properties was used as well. The compounds are a new group of potential antituberculotics.

A proton magnetic resonance spectroscopic study in D₂O of mixtures of fluoxetine hydrochloride (guest) with β-cyclodextrin (host) revealed the existence of two different equilibria for 1:1 inclusion complexes in which –CF₃ substituted ring of the guest is more tightly held by the host cavity. The structures of the two complexes have been proposed which are supported by 2DROESY spectral data. The dissociation constant was also determined.

A number of 2H-pyrrolo[3,4-b] [1,5]benzothiazepine derivatives (PBTAs) 7–25 and the related synthetic intermediates 3-pyrrolyl aryl sulfones (PASs) 26–32 were designed, synthesized and tested as potential anti-HIV-1 agents targeted at the reverse transcriptase (RT). The PBTAs were conceived as tricyclic analogs of nevirapine, pyrrolo[1,2-b] [1,2,5]benzothiadiazepine 5 (PBTD) and pyrrolo[2,1-d] [1,2,5]benzothiadiazepine 6, NNRTIs endowed with potent anti-HIV-1 activities. The majority of tested PBTAs were active against HIV-1-induced cytopathicity in MT-4 cells at concentrations ranging from 0.3 to 40 μM. In particular, compound 10 was the most potent derivative with EC₅₀ = 0.3 μM, comparable to that of nevirapine used as reference drug. In the 3-pyrrolyl aryl sulfones (26–32) series only three sulfones were found active against HIV-1 replication cycle. The following preliminary SAR could be depicted for the title derivatives: i) the conformationally restrained PBTAs are more potent than the corresponding open counterparts (PASs); ii) the DMA group give the highest anti-HIV-1 potency in the PBTAs series; iii) PBTAs and the corresponding thiones are equipotent; iv) an unsubstituted amino group, as part of p-chloroanilino moiety, is a strong determinant for the antiviral activity in the PASs series. The most potent derivatives in cell-based assays were proven to target the RT in enzyme assays. Unfortunately, none of the test compounds inhibited the multiplication of clinically relevant drug-resistant viruses (mutants of HIV-1 carrying K103N and Y181C mutations) at concentrations lower than 30 μM. However, the good results obtained against replication of wt HIV-1, lead us to consider compound 10 as a lead compound for further investigation in this field. In particular, our efforts will be directed to modifications of 10 devoted to obtain new derivatives active against HIV-1 mutant strains.

Several spectrophotometric and HPLC methods are presented for the determination of fenofibrate, vinpocetine and their hydrolysis products. The resolution of either fenofibrate or vinpocetine and their hydrolysis products has been accomplished by using numerical spectrophotometric methods as partial least squares (PLS-1) and principal component regression (PCR) applied to UV spectra; and graphical spectrophotometric methods as first derivative of ratio spectra (¹DD) or first (¹D) and second (²D) derivative spectrophotometry for vinpocetine and fenofibrate, respectively. In addition HPLC methods were developed using ODS column with mobile phase consisting of acetonitrile–water (80:20, v/v, pH 4) with UV detection at 287 nm for fenofibrate and a mobile phase consisting of acetonitrile–10 mM KH₂PO₄, containing 0.1% diethylamine (60:40, v/v, pH 4.6) with UV detection at 270 nm for vinpocetine.

The proposed methods were successfully applied for the determination of each drug and its hydrolysis product in laboratory-prepared mixture and pharmaceutical preparation. The proposed HPLC and derivative spectrophotometric methods were used to investigate the kinetics of acidic and alkaline hydrolytic processes of each drug. The pH-rate profile of hydrolysis of each drug in Britton–Robinson buffer solutions was studied.

Two sensitive spectrophotometric and atomic absorption spectrometric procedures have been developed for determination of cinchocaine hydrochloride (Cin.Cl) in pure form and in pharmaceutical formulation. The spectrophotometric method was based on formation of an insoluble colored ion-associate between the cited drug and tetrathiocyanatocobaltate (CoTC) or hexathiocyanatochromate (CrTC) which dissolved and extracted in an organic solvent. The optimal experimental conditions for quantitative extraction such as pH, concentration of the reagents and solvent were studied. Toluene and iso-butyl alcohol proved to be the most suitable solvents for quantitative extraction of Cin-CoTC and Cin-CrTC ion-associates with maximum absorbance at 620 and 555 nm, respectively. The optimum concentration ranges, molar absorptivities, Ringbom ranges and Sandell sensitivities were also evaluated.

The atomic absorption spectrometric method is based on measuring of the excess cobalt or chromium in the aqueous solution, after precipitation of the drug, at 240.7 and 357.9 nm, respectively. Linear application ranges, characteristic masses and detection limits were 57.99–361.9, 50.40 and 4.22 μg ml^–1 of Cin.Cl, in case of CoTC, while 37.99–379.9, 18.94 and 0.81 μg ml^–1 in case of CrTC.

Human immuno deficiency virus (HIV) weakens the immune system so that many opportunistic infections (OIs) like tuberculosis, hepatitis, bacterial infections etc can develop. In this paper, we designed aminopyrimidinimino isatin lead compound as a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) with broad-spectrum chemotherapeutic properties for the effective treatment of AIDS and AIDS-related OIs. Compound 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-[[N⁴-[3'-(4'-amino-5'-trimethoxybenzyl pyrimidin-2'-yl)imino-1'-(5-methylisatinyl)]methyl]-N¹-piperazinyl]-3-quinoline carboxylic acid (10) emerged as the most potent broad-spectrum chemotherapeutic agent active against HIV, HCV, Mycobacterium tuberculosis and various pathogenic bacteria.

GW196771 is a potent antagonist of the modulatory glycine site of the N-methyl-d-aspartate (NMDA) receptor exhibiting outstanding in vivo profile in different animal models of chronic pain. With the aim to maximize the drug delivery to the target organs a suitable “pro-drug approach” was attempted; in this regards two conjugates of GW196771 with nutrients actively transported into the brain, namely adenosine and glucose, were prepared and investigated. These compounds, were evaluated in vitro in terms of their stability in rat plasma and in vivo on rats. Although an improvement was observed in terms of brain penetration of the esters vs. the parent compound, the amount of the latter did not increase significantly, probably due to some degradation events in the brain, different from the expected ester hydrolysis, resulting in a reduced availability of GW196771.