Farmaco (Societa chimica italiana : 1989)最新文献

A high performance capillary electrophoresis method was developed and validated for purity assessment of minoxidil bulk drug and for determination of minoxidil in Rogaine^®. The principal use of the method was in analyzing illicit minoxidil-containing hair-regrowth samples. Although validated for Rogaine, the procedure proved equally viable on illicit minoxidil-containing preparations. The developed method fulfilled the goal of providing an orthogonal technique to HPLC for confirmation of the presence of minoxidil in these imitations. The method was validated on two instruments, one utilizing EK injection, the other gravity injection. It is selective for minoxidil, which is separated from known process impurities and the single degradation impurity. Validation figures of merit for linearity/recovery (accuracy) and precision were in accordance with current expectations for method validation.

The voltammetric behaviour of montelukast (MKST) was studied using cyclic voltammetry, direct current (DC_t), differential pulse polarography (DPP) and alternating current (AC_t) polarography. MKST exhibited well-defined cathodic waves over the range pH range 1–5. No anodic waves were produced over the same pH range. At pH 1, the analytical pH; the diffusion current constant (Id) was 2.2 ± 0.01 μA l mmol^–1. The current concentration plot was rectilinear over the range 2–20 μg ml^–1 with correlation coefficient (n = 10) of 0.9943. The lower limit of detection (S/N = 2) was 0.2 μg ml^–1 (3.41 × 10^–7 M). The wave has been characterised as being diffusion-controlled, although adsorption phenomenon played a limited role in the electrode reaction. The proposed method was successfully applied to the determination of MKST in commercial tablets, and results were in agreement with those given with a reference HPLC method. The method was further extended to the in vitro determination of the drug in spiked human plasma. The mean % recovery (n = 5) was 101.38 ± 3.85. The number of electrons transferred in the reduction process could be accomplished and a proposal of the electrode reaction was proposed.

A series of 3-(substituted-benzylidene)-1, 3-dihydro-indolin-2-thione derivatives were synthesized as modified congeners of 3-(substituted-benzylidene)-1, 3-dihydro-indolin-2-one series. All the synthesized compounds were examined for their in vitro anti-tyrosine kinase activity against p60^c-Src. The activity results revealed that compounds (Z)-3-(4′-Dimethylamino-benzylidene)-1, 3-dihydro-indolin-2-thione (12) (E)-3-(2′, 6′-Dichloro-benzylidene)-1, 3-dihydro-indolin-2-thione (13) and (E)-3-(3′-Hydroxy-4′-methoxy-benzylidene)-1, 3-dihydro-indolin-2-thione (19) exhibited anti-tyrosine kinase activity with IC₅₀ value of 21.91, 21.20 and 30.92 μM, respectively. These results are comparable to PP1 [1-tert-Butyl-3-p-tolyl-1H-pyrazolo[3, 4-d]pyrimidine-4-yl-amine] (IC₅₀ = 0.17 μM), which is reported as a potent and selective p60^c-Src tyrosine kinase inhibitor. Some thio congeners are found to be more potent than oxo derivatives; however, no significant correlation was observed between the activity profiles of these two series. Docking program was used to investigate the docking mode of each compound at the active site. Among all of the compounds, only (Z)-3-(2′-Chloro-benzylidene)-1, 3-dihydro-indolin-2-one (8) and (E)-3-(3′-Nitro-benzylidene)-1, 3-dihydro-indolin-2-thione (16) were docked at the active site where the PP1 was embedded.

An automated sequential injection (SI) spectrophotometric method for the determination of isoxsuprine hydrochloride is described. The method is based on the condensation of aminoantipyrine with phenols (isoxsuprine hydrochloride) in the presence of an alkaline oxidizing agent (potassium hexacyanoferrate) to yield a pink colored product, the absorbance of which is monitored at 507 nm. Chemical as well as physical SI parameters that affect the signal response have been optimized in order to get better sensitivity, higher sampling rate and better reagent economy. Using the optimized aforesaid parameters, a linear relationship between the relative peak height and concentration was obtained in the range 1–60 mg l^–1. The detection limit (as 3σ value) was 0.3 mg l^–1 and precision was 1.4% and 1.6% at 5 and 10 mg l^–1, respectively. As compared to previous reports, wide linear range, low detection limit, and highly economical reagent consumption are the advantages of this automated method.

A series of derivatives analogous to N^b-benzoyltryptamine were synthesized by the Schotten–Bauman procedure. The products obtained were: N^b-4-methoxy-benzoyltryptamine, N^b-2,4-dimethoxy-benzoyltryptamine, N^b-3,4-dimethoxy-benzoyltryptamine, N^b-3,4-methylenedioxy-benzoyltryptamine and N^b-3,4,5-trimethoxy-benzoyltryptamine. They were characterized through the usual spectrometric methods (UV, IR, ¹H and ¹³C NMR) and showed non-selective relaxant activity in guinea-pig ileum pre-contracted with acetylcholine, histamine and KCl.

A simple and sensitive fluorimetric method for determination of antiviral drugs: ribavirin, acyclovir, and amantadine hydrochloride has been developed. The method was based on the oxidation of these drugs by cerium(IV) in presence of perchloric acid and subsequent monitoring the fluorescence of the induced cerium(III) at λ_excitation 255 and λ_emission 355 nm. Different variables affecting the reaction conditions such as the concentrations of cerium(IV), type and concentration of acid medium, reaction time, temperature, and the diluting solvents were carefully studied and optimized. Under the optimum conditions, linear relationships with good correlation coefficients (0.9978–0.9996) were found between the relative fluorescence intensity and the concentrations of the investigated drugs in the range of 50–1400 ng ml^–1. The assay limits of detection and quantitation were 20–49, and 62–160 ng ml^–1, respectively. The precision of the method was satisfactory; the values of relative standard deviations did not exceed 1.58%. No interference could be observed from the excipients commonly present in dosage forms. The proposed method was successfully applied to the analysis of the investigated drugs in pure and pharmaceutical dosage forms with good accuracy and precision; the recovery percentages ranged from 99.2 to 101.2 ± 0.48–1.30%. The results obtained by the proposed fluorimetric method were comparable with those obtained by the official method stated in the United States Pharmacopoeia.

Derivatives of 2- and 3-benzo[b]furancarboxylic acids were prepared and evaluated for their cytotoxic potential in the National Cancer Institute, Bethesda, USA. Six compounds: 7-acetyl-6-hydroxy-3-methyl-2-benzofurancarboxylic acid (2), 6-hydroxy-7-(p-methoxycinnamoyl)-3-methyl-2-benzofurancarboxylic acid (4), 5-bromo-7-hydroxy-6-methoxy-2-benzofurancarboxylic acid methyl ester (6a), 6-acetyl-5-(O-ethyl-2′-diethylamino)-2-methyl-3-benzofurancarboxylic acid methyl ester (1f), 6-(O-ethyl-2′-diethylamino)-7-p-methoxycinnamoyl)-3-methyl-2-benzofurancarboxylic acid methyl ester hydrochloride (4b), 5-bromo-7-(O-ethyl-2′-diethylamino)-6-methoxy-2-benzofurancarboxylic acid methyl ester (6b) showed significant cytotoxic activities against human cancer cell lines. In addition the crystal structures of 7-methoxy-2-benzofurancarboxylic acid methyl ester (7a) has been solved by X-ray structure analysis of single crystals.

Highly active anti-retroviral therapy (HAART) using reverse transcriptase (RT) and protease (PR) inhibitors and, more recently, inhibitors of the fusion is currently the best clinical approach in combating acquired immunodeficiency syndrome (AIDS), caused by infection from human immunodeficiency virus type 1 (HIV-1). However, this therapy does not completely eradicate the virus, so that resistant strains easily emerge. The above problem calls urgently for research on inhibitors of further viral targets such as integrase (IN), the third enzyme produced by HIV. Recently, our research group was engaged in studies on conformationally restrained cinnamoyl compounds related to curcumin as anti-IN agents. Compounds containing both a 3,4,5-trihydroxyphenyl group and a carboxylic acid function were potent IN inhibitors active against viral replication. More recently, a promising new class of inhibitors synthesized by Merck Company has emerged, which contain aryldiketoacid (ADK) functionality. The ADKs selectively inhibited the stand transfer (ST) step of integration and were proven to be effective IN inhibitors in vivo. Our interest in the field of IN inhibitors led us to designe pyrrole and indole derivatives containing both a cinnamoyl moiety and a diketoacid group. A number of the cited derivatives were proven potent IN inhibitors, which selectively inhibited the ST step at submicromolar concentrations and were effective against virus replication in HIV-1 infected cells.

New 1,4- and 2,4-substituted 1,2,3-triazole derivatives were synthesized and tested as potential BK_Ca channel openers, as a part of a research program, which hypothesizes a pharmacophoric structure containing the 1,2,3-triazole ring. The structure–activity relationships were studied introducing some structural changes concerning molecular geometry and the presence of a hydrogen bond donor as a primary amino group and a phenolic or alcoholic hydroxy function. The compounds were prepared by nucleophilic substitution on the 1,2,3-triazole ring and by 1,3-dipolar cycloaddition of azides to selected alkynes and to phenylacetone. The new compounds tested on rat aortic rings did not exhibit any significant vasorelaxing activity.

New racemic 1,4-disubstituted piperazines chemically named ethyl 2-[(4-pyrimidin-2yl-piperazine-1yl)carbonyl]C3-C5-alkanoates 1-7 were synthesized. The compounds were resolved into enantiomers on cellulose tris(4-methylbenzoate) and amylose tris(3,5-dimethylphenylcarbamate) stationary phases using hexane/propan-2-ol mobile phases. The optimum separation conditions for the compounds were obtained on cellulose tris(4-methylbenzoate) with 5% of 2-propanol in hexane. The relationship between structural and chromatographic parameters is discussed.