1-Benzopyran-4-one antioxidants as aldose reductase inhibitors.

Starting from the inhibitory activity of the flavonoid Quercetin, a series of 4H-1-benzopyran-4-one derivatives was synthesized and tested for inhibition of aldose reductase, an enzyme involved in the appearance of diabetic complications. Some of the compounds obtained display inhibitory activity similar to that of Sorbinil but are more selective than Quercetin and Sorbinil with respect to the closely related enzyme, aldehyde reductase, and also possess antioxidant activity. Remarkably, these compounds possess higher pKa values than carboxylic acids, a characteristic which could make the pharmacokinetics of these compounds very interesting. Molecular modeling investigations on the structures of inhibitors bound at the active site of aldose reductase were performed in order to suggest how these new inhibitors might bind to the enzyme and also to interpret structure-activity relationships.

Inhibition of lens aldose reductase by biflavones from Ouratea spectabilis.

Two biflavonoids were isolated from the EtOH extract from leaves of Ouratea spectabilis. Their structures were established to be the novel 6,6"-bigenkwanin and 7,7"-dimethoxyagathisflavone on the basis of spectroscopic data. The inhibition of bovine lens aldose reductase exerted by these biflavones has been studied.

Activity of polyphenolic crude extracts as scavengers of superoxide radicals and inhibitors of xanthine oxidase.

In view of the pharmacological interest in phenolic substances, we have determined the total amount of anthocyanins and polyphenols present in the berries of several cultivars of Ribes, Rubus, and Vaccinium genera. The in vitro antiradical activity of the crude extracts on chemically-generated superoxide radicals as well as the inhibitory activity towards the enzyme xanthine oxidase were studied. All the crude extracts examined showed a remarkably high activity towards chemically-generated superoxide radicals. The activities were greater than those expected on the basis of the quantities of anthocyanins and polyphenols present in the samples. Furthermore, the extracts showed a certain inhibitory activity towards xanthine oxidase. Ribes nigrum extracts exhibit the highest activity, being the richest in both anthocyanins and polyphenols. On the other hand, Ribes rubrum extracts seem to contain more active substances than the other crude extracts.

Studies on the genotoxic properties of essential oils with Bacillus subtilis rec-assay and Salmonella/microsome reversion assay.

Genotoxic properties of essential oils from Anthemis nobilis L., Artemisia dracunculus L., Salvia officinalis L., Salvia sclarea L., Satureja hortensis L., Satureja montana L., Thymus capitatus L., Thymus citriodorus Schreb., Thymus vulgaris L., Citrus bergamia Risso, were studied with Bacillus subtilis rec-assay and Salmonella/microsome reversion assay. The essential oil of Artemisia dracunculus L. "Piemontese" turned out to be active in the rec-assay but not in the Salmonella test. DNA-damaging activity was demonstrated to be due to the estragol component of the oil. Advantages of the combined use of these two short-term microbial assays in genotoxic studies are discussed.

Sedative, anti-inflammatory and anti-diuretic effects induced in rats by essential oils of varieties of Anthemis nobilis: a comparative study.

The pharmacological properties of essential oils obtained from two varieties of Anthemis nobilis was studied. The two varieties, named "white-headed" or double flowered and "yellow-headed", present considerable morphological differences and yield essential oils with different composition. These essential oils proved to possess interesting anti-inflammatory and sedative properties, especially that derived from the "White-headed" variety.

Preparation and physicochemical properties of uracil derivatives with potential biological activity.

The characterization of mono- and dimethylated 5-substituted uracils was re-examined. Analysis of their physicochemical properties (pKa, U.V., delta 1H-N.M.R.) affords insight into the structural characteristics of 5-substituted uracil alkylated at the ring nitrogens.

Antimycotic action of methyl substituted N-(5-pyrimidinyl)benzenesulfonamide derivatives.

Some series of N-(5-pyrimidinyl)benzenesulfonamide variously methylated at the ring and/or sulfonamidic nitrogens and substituted at the benzene with NO2 or NH2 were synthesized and studied spectrometrically (N.M.R). When tested on several strains of Candida albicans and Candida tropicalis, some of the compounds exhibited very slight antimycotic activity.

Antimycotic action of alkyl derivatives of 5-(benzenesulfonamide)-1,2,3,4-tetrahydro-2-thioxo-4-pyrimidinon e.

Several series of mono-, di- and trimethyl derivatives of N-(6-amino-1,2,3,4-tetrahydro-4-oxo-2-thioxo-5-pyrimidinyl)benzene sulfonamide substituted at the benzene ring (Z), were synthesized and studied spectrophotometrically. The spectral and physical data enabled the structures of the methyl derivatives obtained by methylating (Z) to be identified. When assayed biologically as antimycotics, a small percentage of the substances exhibited mild fungicide activity.

Antimycotic action of some amino-N-(5-pyrimidinyl)benzenesulfonamides.

2-, 3- and 4-amino-N-(6-amino-1,4-dihydro-4-oxo-2-mercapto (or alkylthio)-5-pyrimidinyl)benzenesulfonamides were synthesized and biologically tested on different strains of Candida albicans and Candida tropicalis. Some of the 4-aminoderivatives were also tested for antibacterial properties on numerous bacterial strains. Antimycotic activity of 4-amino compounds, expressed as MIC, is around 50 micrograms/ml and higher than that of both 2-amino- and 3-aminoderivatives. In all these compounds alkyl chain length does not seem to have any notable effects on biological activity, an exception being made for some aralkyl compounds. Antibacterial activity of 4-aminoderivatives is very low for all strains tested.

[Molecular structure with potential inhibitory action on the biosynthesis of FAH4]. / Strutture molecolari a potenziale azione inibitrice della biosintesi del FAH4.

Molecules formed by two pharmacophoric synthons--4-H2N--C6H4--SO2NH--and 2,4-diaminopyrimidine--were prepared. These structural units, with sulphamidic and antifolic action respectively, are bound without mutual electronic interaction, as demonstrated by their experimental electronic indices. The compounds were tested for activity on several bacterial strains and their biological activity was compared with that of molecular combinations formed by 4-aminobenzensulphonamide and substituted 2,4-diaminopyrimidines, to discover whether these two pharmacophoric synthons, so bound, are synergic.

[Structure-activity relationships in N1-acetylderivatives of sulpha drugs].

The N1-acetylderivatives (ASA) of sulphanylamides (SA) were prepared and their stability to hydrolysis was evaluated together with the spectroscopic and antibacteric activity parameters, with the aim both of obtaining electronic structure-activity relationships and of comparing these results with those previously found for SA. From our results it appears that: a) the stability to hydrolysis is dramatically reduced on passing from the aqueous medium (pH 7) to the culture broth, and that b) in general, the ASA examined do not show any greater antibacterial activity with respect to the parent compounds, as suggested by the values of the spectroscopic indices-taken as experimental electronic indices. This result is in full agreement with the structure-activity relationships previously proposed fo the sulpha drugs.

Electronic aspects of the antibacterial action of sulfanilamides.

Intramolecular interactions in N1-substituted sulfanilamides (SA) can rationalize the trend of their antibacterial powers with the use of a resonance scheme, derived from d orbital symmetry and tested with an extensive spectroscopic investigation on amidic, imidic, and anionic SA. On quantitative grounds, a good relationship is presented between the antibacterial power and the proton chemical shift of the p-amino group. The electronic features for high activity are described.

Antibacterial activity and chemical reactivity of sulphanylamides. Rate constants of alkaline hydrolysis of N4-acetylsulphanylamides.

The alkaline deacylation rate constants of a collection of N4-acetylderivatives of acidic and non-acidic sulphonamides (SA) clearly show a definite trend due to the intramolecular effects induced by the different substitutions on the N1 nitrogen. The rate constant is interpreted as a reactivity index of the corresponding non-acetylated compound, and is found to be strictly correlated with the electron-availability of the p-amino group; thus providing an interesting correlation with the antibacterial activity of these drugs. Moreover, the reported experiments corroborate early predictions that the greatest reactivity of the p-amino group pertains to p-aminobenzoate (PAB) in the series of chemically related compounds, and that SA anions show the highest chemical and electronic resemblance to the essential metabolite (PAB); thus the high antibacterial activity of SA anions correctly corresponds to its close resemblance to the metabolite.

The role of anionic, imidic and amidic forms in structure-activity relationships. Conjugation and bacteriostatic activity in sulphonamides.

The electronic structures of anionic, imidic and amidic forms of sulphonamides were investigated and compared by means of I.R., Raman and U.V. spectroscopy. Indices reflecting the electronic situation of the common moiety p-H2N-C6H4-SO2 was a whole, although not necessarily related, physically, to any event taking place in the biological processes, were found to correlate with the in vitro bacteriostatic activity of the specific individual forms. The influence of N1-substituents both on the SO2 electronic features and on the coupling between the para amino group and the phenyl ring was discussed. It resulted that the most active chemical species, in this class of compounds, are characterized, electronically, by the most electron-rich common moiety and, in particular, by the most negative oxygens in the SO2 group and the most available (less engaged) lone-pair in the rho-amino group. These conclusions give a new settlement both to the problem of resonance and to the relation between resonance effects and bacteriostatic activity in this class of compounds.

The role of anionic, imidic, and amidic forms in structure-activity relationships. Correlation of electronic indices and bacteriostatic activity in sulfonamides.

The problem of structure-activity relationships in sulfonamide type compounds is tackled on the ground that both bacteriostatic activities and structural indices must be referred to the specific individual forms assumed by sulfa drugs in the active solutions. The frequency value of the symmetric stretching mode of the sulfonyl group upsilons (SO2) is chosen as a suitable electronic index and measured for the individual active forms in aqueous and Me2SO solutions. The linear correlation that exists between bacteriostatic parameter and vibration frequency (over the complete range of data at present available) proves a strict relationship between electronic structure and bacteriostatic activity in this class of drugs. Furthermore, it justifies the assumption used for the calculation of the bacteriostatic activity of the anionic form; i.e., in equilibrium with a very active species (the anion) a less active species (the neutral form) gives a negligible contribution or does not contribute at all to the total activity. The results can be summarized as follows: the lower the frequency of the symmetric stretching mode of the SO2 group of any active species of sulfonamide type compounds, the higher its bacteriostatic activity. The existence of a clear structure-activity correlation demonstrates that the whole class of compounds, whatever their form, has a single mechanism of action, while incontrovertible deviations from the general trend indicate differences or complications in the mechanism itself, but does not demonstrate that the group on which the structural index is localized plays a dominant role in the biological process. The usefulness of pKa and NH2 proton chemical shift of precursor amine as indirect indices of the electronic structure of the anionic forms is explored on extensive sets of available data.