Farmaco (Societa chimica italiana : 1989)最新文献

Recently a series of H₃-antagonists related to Imoproxifan was realised (I); in these products the oxime substructure of the lead was constrained in NO-donor furoxan systems and in the corresponding furazan derivatives. In this paper, a new series of compounds derived from I by substituting the imidazole ring with the ethoxycarbonylpiperazino moiety present in the non-imidazole H₃-ligand A-923 is described. For all the products synthesis and preliminary pharmacological characterisation, as well as their hydrophilic–lipophilic balance, are reported. The imidazole ring replacement generally results in a decreased H₃-antagonist activity with respect to the analogues of series I and, in some cases, induces relaxing effects on the electrically contracted guinea-pig ileum, probably due to increased affinity for other receptor systems.

Abstract

Notwithstanding the criticism to the so called “ cholinergic hypothesis”, the therapeutic strategies for the treatment of Alzheimer's disease (AD) have been mainly centered on the restoration of cholinergic functionality and, until the last year, the only drugs licensed for the management of AD were the acetycholinesterase (AChE) inhibitors. Target enzyme AChE consists of a narrow gorge with two separate ligand binding sites: an acylation site at the bottom of the gorge containing the catalytic triad and a peripheral site located at the gorge rim, which encompasses binding sites for allosteric ligands. The aim of this short review is to update the knowledge on heterocyclic AChE inhibitors able to interact with the two sites of enzymes, structurally related to the well known inhibitors physostigmine, rivastigmine and propidium. The therapeutic potential of the dual site inhibithors in inhibiting amyloid-ß aggregatrion and deposition is also briefly summarised.

A 2.0 ns unrestrained Molecular Dynamics was used to elucidate the geometric and dynamic properties of the HSA binding sites. The structure is not stress affected and the rmsds calculated from the published crystallographic data are almost constant for all the simulation time, with an averaged value of 2.4Å. The major variability is in the C-terminus region. The trajectory analysis of the IIA binding site put in evidence fast oscillations for the Cγ@Leu203···Cγ@Leu275 and Cγ@Leu219···Cγ@Leu260 distances, with fluctuations around 250 ps, 1000 ps and over for the first, while the second is smoothly increasing with the simulation time from 7 to 10Å. These variations are consistent with a volume increase up to 20% confirmed by the inter-domain contacts analysis, in particular for the pair O@Pro148···Oγ@Ser283, representing the change of distance between IB-h9 and IIA-h6, O@Glu149···Oγ@Ser189 for sub-domains IB-h9/IIA-h1 and N@Val339···Oδ2@Asp447 sub-domains IIB-h9/IIIA-h1. These inter-domain motions confirm the flexibility of the unfatted HSA with possible binding site pre-formation.

Two simple, rapid and sensitive spectrophotometric methods have been proposed for the determination of lisinopril in pure form and pharmaceutical formulations. The methods are based on the charge transfer complexation reaction of the drug with 7,7,8,8,tetracyanoquinodimethane (TCNQ) and p-chloranilic acid (pCA) in polar media. The lisinopril–TCNQ and lisinopril–pCA charge transfer complexes dissociate in acetone and methanol, respectively, and yield coloured TCNQ and pCA radical anions which are measured spectrophotometrically at 743 and 525 nm. Under optimised experimental conditions, Beer's law is obeyed in the concentration range of 2–26 and 25–300 μg ml^–1 with molar absorptivity of 1.432 × 10⁴ and 1.192 × 10⁴ l mol^–1 cm^–1 for TCNQ and pCA methods, respectively. Both the methods have been applied to the determination of lisinopril in pharmaceutical dosage forms. Results of analysis are validated statistically.

The influence of temperature and relative humidity on the stability of aztreonam in AZACTAM was investigated. Changes of the concentration of aztreonam were followed using the HPLC method with UV detection. The first-order rate constants of the reversible reaction of isomerization Z-aztreonam $\stackrel{}{\rightleftharpoons }$ E-aztreonam and the parallel reaction Z-aztreonam → products were determined at RH = 76.4% and T = 313, 323, 333, 343 and 353 K, and at T = 343 K and RH = 50.9%, 60.5%, 66.5% and 76.4%. The thermodynamic parameters—energy, enthalpy and entropy of these reactions were calculated.

Sodium tetraphenylborate and phosphotungstic acid were used as titrants for the conductimetric determination of phenylpropanolamine HCl (PPA.Cl), ranitidine HCl (Ra.Cl), hyoscyamine HBr (Hy.Br) and betaine HCl (Be.Cl) through ion-associate complex formation. The molar combining ratio and the solubility products of the formed ion-associates were studied and calculated. The suggested method has been applied to the determination of the mentioned drugs in their pure state and pharmaceutical preparations with mean recovery values of 97.71–102.97% and relative standard deviations 0.25–0.85%. The accuracy of the method is indicated by excellent recovery and low standard deviation. The results are compared with the pharmacopoeial or the official methods.

Multivariate chromatographic calibration technique was developed for the quantitative analysis of binary mixtures enalapril maleate (EA) and hydrochlorothiazide (HCT) in tablets in the presence of losartan potassium (LST). The mathematical algorithm of multivariate chromatographic calibration technique is based on the use of the linear regression equations constructed using relationship between concentration and peak area at the five-wavelength set. The algorithm of this mathematical calibration model having a simple mathematical content was briefly described. This approach is a powerful mathematical tool for an optimum chromatographic multivariate calibration and elimination of fluctuations coming from instrumental and experimental conditions. This multivariate chromatographic calibration contains reduction of multivariate linear regression functions to univariate data set. The validation of model was carried out by analyzing various synthetic binary mixtures and using the standard addition technique. Developed calibration technique was applied to the analysis of the real pharmaceutical tablets containing EA and HCT. The obtained results were compared with those obtained by classical HPLC method. It was observed that the proposed multivariate chromatographic calibration gives better results than classical HPLC.

To continue our systematic SAR studies, two series of N-benzyl- (X = CH₂) and N-aminophenyl- (X = NH) derivatives of 2-azaspiro[4.4]nonane (1a–1j) and 2-azaspiro[4.5]decane-1,3-dione (2a–2j) were synthesized, and evaluated in maximum electroshock seizure (MES), subcutaneous pentylenetetrazole (sc.MET) and rotorod (TOX) tests for their anticonvulsant activity. Among those derivatives, the most potent N-aminophenyl-2-azaspiro[4.4]nonane-1,3-dione 1j had ED₅₀ = 76.27 mg kg^–1. X-ray structures for two pairs of derivatives with a different linker were solved. Then 3-D data for the active 1j versus less active 2j, both having an imine linker (X = NH), and the respective parent of compounds with a methylene linker (X = CH₂) (1a and 2a) were discussed.

Simple, sensitive and economical simultaneous volumetric and spectrophotometric methods for the determination of captopril have been developed. The methods were based on the reaction of captopril with potassium iodate in HCl medium. Amaranth was used as indicator to detect the end-point of the titration in aqueous layer. The iodine formed during the titration was extracted into CCl₄ and subsequently determined spectrophotometrically at 510 nm. The Beer's law was obeyed in the concentration range of 120–520 μg ml⁻¹. Rigorous statistical analyses were performed for the validation of the proposed methods. The proposed methods were successfully applied to the determination of captopril in dosage forms. Comparison of the means of the proposed procedures with those of reference methods using point and interval hypothesis tests showed no statistically significant difference.