Farmaco (Societa chimica italiana : 1989)最新文献

Piroxicam is a poorly soluble, highly permeable drug and the rate of its oral absorption is often controlled by the dissolution rate in the gastrointestinal. The poor dissolution rate of water-insoluble drugs is still a major problem confronting the pharmaceutical industry. There are several techniques to enhance the dissolution of poorly soluble drugs. Among them, the technique of liquisolid compacts is a promising technique towards such a novel aim. In this study, the dissolution behaviour of piroxicam from liquisolid compacts was investigated in simulated gastric fluid (SGF, pH 1.2) and simulated intestinal fluid (SIF, pH 7.2). To this end, several liquisolid tablets formulations containing various ratios of drug:Tween 80 (ranging from 10% to 50% w/w) were prepared. The ratio of microcrystalline cellulose (carrier) to silica (coating powder material) was kept constant in all formulations. The results showed that liquisolid compacts demonstrated significantly higher drug release rates than those of conventionally made (capsules and directly compressed tablets containing micronized piroxicam). This was due to an increase in wetting properties and surface of drug available for dissolution.

A new series of potential adenosine receptor antagonists with a [1,2,4]-triazolo-[3,4-f]-purine structure have been synthesized, and their affinities at the four adenosine receptor subtypes (A₁, A_2A, A_2B and A₃) have been evaluated. The design was based on the demonstrated approach to novel A₃ adenosine receptor antagonists of adding a third ring to the xanthine structure. Unfortunately, all the synthesized compounds were completely inactive at all four adenosine receptor subtypes independently of their substitutions. Preliminary molecular modeling investigation has demonstrated that only a low degree of steric and electrostatic complementarity has been observed for all the new synthesized triazolo-purines with respect to other structurally related A₃ receptor antagonists. This analysis yielded valuable information about structure–activity relationships and further design of potential adenosine receptor antagonists.

Some novel 2-amino-6-aryl-4-(2-thienyl)pyrimidines were synthesized from 3-aryl-1-thien-2ylprop-2-en-1-ones and guanidine hydrochloride in presence of alkali by conventional heating in alcoholic medium and microwave heating in solvent-free conditions. The compounds were evaluated for in vitro anti-bacterial activity. The anti-bacterial data revealed that compounds 5a–e had better activity against tested Gram-positive organisms than the reference ciprofloxacin and norfloxacin. However, the compounds were nearly inactive against Gram-negative bacteria. Compounds 5c and e were the most active compounds against Gram-positive bacteria.

A series of N-cycloalkenyl-2-acylalkylidene-2,3-dihydro-1,3-benzothiazoles 5a–j, N-cycloalkyl-2-acylalkylidene-2,3-dihydro-1,3-benzothiazoles 8a–e, and N-alkyl-2-acylalkylidene-2,3-dihydro-1,3-benzothiazoles 8f–h, were synthesized and tested for in vitro antibacterial and antifungal activities against four gram-positive and five gram-negative bacteria (Bacillus subtilis 6633, Enterococcus faecalis 29212, Staphylococcus aureus 6538, Staphylococcus aureus 25923, Escherichia coli 25922, Acinetobacter calcoaceticus a1, A. calcoaceticus a2, Pseudomonas aeruginosa 27835, Klebsiella oxytoca 49131), four yeast-like fungi and one fungus (Candida tropicalis 750, C. albicans 14053, C. albicans 10231, Criptococcus laurentii 18803, and Saccharomyces cerevisiae). Microdilution broth and agar dilution methods were used for antimicrobial tests. The findings obtained showed that some of the tested compounds 5 and 8 were effective against some of the bacterial strains used, whereas, only compounds 8b–g exhibited a moderate antifungal activity against the yeast strains evaluated.

A series of sulfonamide chalcone derivatives were synthesized and investigated for their abilities to inhibit β-hematin formation in vitro and their activity against cultured Plasmodium falciparum parasites. Inhibition of β-hematin formation was minimal in the aromatic ring of the chalcone moiety as it appeared for compounds 4b, 4d-f, and greatest with compounds 4g (IC₅₀ 0.48 μM) and 4k (IC₅₀ 0.50 μM) with a substitution of 3,4,5-trimethoxyl and 3-pyridinyl, respectively. In this study, the most active compound resulted 1[4'-N(2'',5''-dichlorophenyl) sulfonyl-amidephenyl]-3-(4-methylphenyl)-2-propen-1-one 4i, effective as antimalarial by the inhibition of cultured P. falciparum parasites (1 μM). These studies open up the novel possibility of development of sulfonamide derivatives as antimalarials that target β-hematin formation and the inhibition of the development of cultured P. falciparum parasites, which should help delay the rapid onset of resistance to drugs acting at only a single site. Results with these assays suggest that chalcones exert their antimalarial activity via multiple mechanisms.

In this research, the effect of mucoadhesive polymers such as hydroxyl propyl methyl cellulose (HPMC) with viscosity grade 60 and 500 mPas, sodium carboxy methyl cellulose (NaCMC) and carbopol 934 (Cp 934) alone or in combination with each other on the release profile of prednisolone was studied and mucoadhesion strength of these buccoadhesive formulations was evaluated. The results showed that the release of prednisolone from HPMC with viscosity grade 60 mPas and Cp 934 alone was fast and their mucoadhesion strengths was low. On the other hand, the release rates of prednisolone from the HPMC viscosity grade 500 mPas and NaCMC and mucoadhesion strengths were moderate and suitable. The results showed that with different blends of HPMC viscosity grade 500 mPas or NaCMC and Cp 934 with increasing in HPMC or NaCMC/Cp 934 ratio a remarkable decrease in the rate of drug release and an appreciable increase in the mucoadhesion strength was observed. Except from the formulations prepared with HPMC viscosity grade 60 and 500 mPas, other formulation had more fluctuations in release profiles and their kinetics of release were not fitted to zero order model.

A new series of N-substituted imide derivatives have been synthesized by treating phthalic anhydride, naphthalic anhydride and their substituted derivatives with 2-hydrazino-1-imidazoline hydrobromide, various para-substituted aryl amines, aminoglutethimide and 2,4-dinitrophenyl hydrazine. Compounds 9, 10, 12, 18, 19, 23, 24 and 34–36 have been selected and screened for antineoplastic activity by National Cancer Institute, Bethesda, USA. Some newer aminoglutethimide derivatives 37–39 have also been prepared in order to study the effect of N-substitution on its pharmacological profile for the treatment of carcinoma. These compounds (37–39) have exhibited weak inhibition of human placental aromatase as compared to aminoglutethimide.

A sensitive, selective, precise and stability-indicating high-performance thin-layer chromatographic method for analysis of metadoxine both as a bulk drug and in formulations was developed and validated. The method employed TLC aluminium plates precoated with silica gel 60F-254 as the stationary phase. The solvent system consisted of acetone–chloroform–methanol–ammonia (7.0: 4.0: 3.0: 1.2, v/v/v/v). Densitometric analysis of metadoxine was carried out in the absorbance mode at 315 nm. This system was found to give compact spots for metadoxine (R_f value of 0.45 ± 0.02, for six replicates). Metadoxine was subjected to acid, alkali and neutral hydrolysis, oxidation, dry and wet heat treatment and photo and UV degradation. The drug undergoes degradation under all stress conditions. Also, the degraded products were well resolved from the pure drug with significantly different R_f values. The method was validated for linearity, precision, robustness, LOD, LOQ, specificity and accuracy. Linearity was found to be in the range of 100–1500 ng/spot with significantly high value of correlation coefficient r² = 0.9997 ± 1.02. The linear regression analysis data for the calibration plots showed good linear relationship with r² = 0.9999 ± 0.58 in the working concentration range of 200–700 ng/spot. The mean value of slope and intercept were 0.11 ± 0.04 and 18.73 ± 1.89, respectively. The limits of detection and quantitation were 50 and 100 ng/spot, respectively. Statistical analysis proves that the method is repeatable and specific for the estimation of the said drug. As the method could effectively separate the drug from its degradation products, it can be employed as a stability-indicating one. Moreover, the proposed HPTLC method was utilized to investigate the kinetics of acid and base degradation process. Arrhenius plot was constructed and activation energy was calculated respectively for acid and base degradation process.

The crystal structure of Acetylcholine Binding Protein (AChBP), homolog of the ligand binding domain of nAChR, has been used as model for computational investigations on the ligand–receptor interactions of derivatives of 6-chloropyridazine substituted at C₃ with 3,8-diazabicyclo[3.2.1]octane, 2,5-diazabicyclo[2.2.1]heptane and with piperazine and homopiperazine, substituted or not at N₄. The ligand–receptor complexes have been analyzed by docking techniques using the binding site of HEPES complexed with AChBP as template. The good relationship between the observed binding affinity and the calculated docking energy confirms that this model provides a good starting point for understanding the binding domain of neuronal nicotinic receptors. An analysis of the possible factors significant for the ligand recognition has evidenced, besides the cation–π interaction, the distance between the chlorine atom of the pyridazinyl group and the carbonylic oxygen of Leu B112 as an important parameter in the modulation of the binding energy.

Marrubiin, a furane labdane diterpene, is the main analgesic compound present in Marrubium vulgare, a medicinal plant used in Brazil and other countries to treat several ailments. Considering its important pharmacological action, as well as its high yield, some structural modifications were performed in order to obtain more active compounds. Success was obtained in reducing the lactonic function, in the formation of marrubiinic acid and two esterified derivatives, which exhibited significant analgesic effect against the writhing test in mice. Marrubiinic acid showed better activity and excellent yield, and its analgesic effect was confirmed in other experimental models of pain in mice, suggesting its possible use as a model to obtain new and potent analgesic agents.