Luciano Antolini

Synthesis and activity of a new series of chalcones as aldose reductase inhibitors

A new series of chalcone derivatives has been synthesized and tested in vitro in order to assess their ability to inhibit aldose reductase enzyme (ALR2) and their specificity towards the target enzyme with respect to other oxidoreductases, such as aldehyde reductase, sorbitol dehydrogenase, and glutathione reductase. All the compounds display affinity for ALR2. The X-ray crystal structure of 1-(2,4-dihydroxyphenyl)-3-(2-methoxyphenyl)propen-1-one was determined.

Isolation and pharmacological activities of the Tecoma stans alkaloids

Tecoma stans is a plant traditionally used in Mexico for the control of diabetes. Amongst the alkaloids isolated from the plant harvested in Egypt, Tecomine was shown to be one of the compounds responsible for the hypoglycemic action. Given the interest in substances able to treat type II diabetes, we isolated the main alkaloids present in the plant growing in Egypt and Brazil and tested them in vivo on db/db mice. Contrary to previous literature reports on different animal models, Tecomine was unable to modify glycemia; the only effect seen being a decrease in plasma cholesterol levels. On the contrary, when tested in vitro on glucose uptake in white adipocytes, the compound showed a marked effect. The two other alkaloids isolated, namely 5beta-Hydroxyskitanthine, early called Base C, and Boschniakine were inactive both in vivo and in vitro assays.

Structural bases for the inhibition of aldose reductase by phenolic compounds.

Aldose reductase (ALR2) is an enzyme involved in the development of long-term diabetic complications. In the search for aldose reductase inhibitors less acidic than carboxylic acids, phenolic compounds related to benzopyran-4-one and chalcone are particularly interesting because they possess good inhibitory properties. In order to investigate the similarities between these two classes of compounds and to provide a structural basis for their inhibition of ALR2, the existing structure-activity relationships were reconsidered. To this end, the acidity constants of a set of chalcones were measured and compared with those of benzopyran-4-one derivatives. Then, having established the relevant protonation state of these phenolics at physiological pH, a conformational analysis was performed on the most active benzopyran-4-one and chalcone derivatives and the results were compared with the crystal structures of some analogues. Finally, molecular docking of the most active chalcone into the ALR2 binding site was performed, and the structure of the enzyme-inhibitor complex was compared with that of the complex formed between ALR2 and a previously-obtained benzopyran-4-one derivative.

Characterization and pharmacological actions of tecostanine, an alkaloid of Tecoma stans

Tecostanine (1) was isolated from Tecoma stans leaves. Its sterochemistry was elucidated as well as its antihyperglycemic activity and its affinity to opioid and nicotinic receptors. The oxalate salt of 1 did not significantly affect blood glucose levels in normoglycaemic and hyperglycaemic rats. It did not appear to interact with opioid receptors (mu type) and showed only moderate affinity to the nicotinic receptor.

Synthesis, characterization, crystallographic analysis, antifungal and genotoxic properties of some 1-methyl-1H-imidazoles

Summary A number of 1-methyl-1 H -imidazole derivatives and some of their oxygenated products were synthesized. An HPTLC technique for following the oxidation reactions in the different experimental conditions used was applied. The X-ray crystal structures of 1-methyl-2-methylsulfanyl-5-nitro-1 H -imidazole, 2-methanesulfinyl-1-methyl-5-nitro-1 H -imidazole and 2-methanesulfonyl-1-methyl-5-nitro-1 H -imidazole were determined. The compounds obtained were investigated for antimycotic and genotoxic activities. The compounds tested were found to exert very low growth inhibition against yeasts and moulds. Moderate antifungal properties against dermatophytes were demonstrated for 5-nitro derivatives. 2-Methanesulfonyl-1-methyl-5-nitro-1 H -imidazole was the most active substance. All 5-nitroimidazoles were genotoxic in Bacillus subtilis rec -assay, Salmonella microsome test and in Saccharomyces cerevisiae mitotic segregation assay. Structure-activity relationships are discussed.

Synthesis and α-adrenoceptor blocking activity of the enantiomers of benzyl-(2-chloroethyl)-[2-(2-methoxyphenoxy)-1-methylethl]amine hydrochloride

The enantiomers of benzyl-(2-chloroethyl)-[2-(2-methoxyphenoxy) -1-methylethyl]amine hydrochloride (1, CM18) were synthesized and studied pharmacologically for their irreversible antagonism at rat vas deferens alpha-adrenoceptors. In addition, assignment of the absolute configuration of the two enantiomers of 1 was made by X-ray crystallographic analysis performed on the intermediate amine (+)-2 hydrochloride. The enantiomer (R)-(+)-1 [(R)-(+)-CM18] (a) had a 10-fold preferential blocking activity for alpha 1-versus alpha 2-adrenoceptors, (b) discriminated, like racemic 1, between two possible alpha 1-adrenoceptor subsites/subtypes, with a selectivity ratio of 6.5 and (c) was 10-23 times as potent as the (S)-(-)-enantiomer at alpha 2- and alpha 1-adrenoceptors. Thus, it may be a valuable tool for the characterization of rat vas deferens alpha 1-adrenoceptor subtypes.

Synthesis, absolute configuration and antimuscarinic activity of the enantiomers of [1-(2,2-diphenyl-[1,3]dioxolan-4-yl)-ethyl]-dimethyl-amine

Methylation of the carbon atom C of compound 1, a potent and not selective muscarinic antagonist, was carried out. The resulting diastereomers were separated and the corresponding racemate further resolved to give four enantiomers, which were tested both as hydrogen oxalate and methiodide salts. The pharmacological results obtained at M1, M2 and M3 muscarinic receptor subtypes, show that methylation at C1, depending on the stereochemistry, increases antagonist potency, having thus the same effect of nitrogen quaternization. These results may well lead to the development of new potent antimuscarinic drugs lacking a cationic head.