Stereoselective binding of 2-(4-biphenylyl)-3-substituted-3-hydroxypropionic acids on an immobilised human serum albumin chiral stationary phase.

A series of 2-(4-biphenylyl)-3,3'-hydroxy-substituted phenyl propionic acid, with anti-inflammatory properties, bearing two chiral centres, were studied by HPLC upon HSA-CSP (human serum albumin-based chiral stationary phase). The compounds were analysed in their stereoisomeric erythro and threo forms. The study involved the enantioselective analysis on HSA-CSP, the determination of the racemate lipophilicity (log k'(w)), a QSRR (quantitative structure-retention relationship) analysis and CD study for the assessment of the absolute configuration of the most retained enantiomer. Lipophilicity was found to be an important factor affecting the affinity of the compounds for the HSA stationary phase, but electronic properties seemed to play a role. The position of the substituent of the phenyl group on carbon 3 was found important to modulate stereoselective interaction, the highest value of enantioselectivities being found for the erythro ortho-substituted phenyl derivatives. The previously proposed two steps mechanism of enantiodiscrimination for cyclohexylphenyl substituted derivatives was confirmed for this series of derivatives bearing the biphenylyl moiety.

Synthesis and antimicrobial activity of new diazoimidazole derivatives containing an N-acylpyrrolidine ring.

A series of 4-diazoimidazole-5-carboxamides bearing in position 2 lipophilic substituents was synthesized and their antimicrobial activity was evaluated in vitro against pathogenic Gram-positive, Gram-negative bacteria and fungi. Some compounds presented antifungal activity, particularly two derivatives (1g and 1h) showed good MIC values (10-50 microg/ml) against both moulds and yeasts.

Stereoselective binding of 2,3-substituted 3-hydroxypropionic acids on an immobilised human serum albumin chiral stationary phase: stereochemical characterisation and quantitative structure-retention relationship study.

The binding characteristics of a series of 2,3-substituted 3-hydroxypropionic acids, with anti-inflammatory properties, bearing two chiral centres, were studied by HPLC upon HSA (human serum albumin)-based stationary phase. The compounds were analysed in their stereoisomeric erythro and threo forms and the chromatographic conditions for enantioseparation of the erythro and threo forms were studied on human serum albumin stationary phase. The enantiomer elution order was determined by injection of the enriched samples or by carrying out the CD spectra of each enantiomeric fraction. The absolute configuration of the single enantiomers was assigned on the basis of their CD spectra. A QSRR study was performed by subjecting the chromatographic data of the compounds to multiparameter regression analysis against various molecular descriptors to have insight into the chiral recognition mechanism. The lipophilicity appeared to be the most important parameter in determining the affinity to the protein, the compounds' capacity factors being linearly correlated to the experimental RP-HPLC partition coefficients (log k'w). The enantioselectivity factors (alpha) related to the enantiomers of the erythro and threo forms were studied taking into consideration both the physico-chemical parameters and the conformational behaviour of the compounds.

Synthesis and antagonistic activity at muscarinic receptor subtypes of some 2-carbonyl derivatives of diphenidol.

A series of 2-carbonyl analogues of the muscarinic antagonist diphenidol bearing 1-substituents of different lipophilic, electronic, and steric properties was synthesized and their affinity for the M2 and M3 muscarinic receptor subtypes was evaluated by functional tests. Two derivatives (2g and 2d) showed an M2-selective profile which was confirmed by functional tests on the M1 and M4 receptors. A possible relationship between M2 selectivity and lipophilicity of the 1-substituent was suggested by structure-activity analysis. This work showed that appropriate structural modification of diphenidol can lead to M2-selective muscarinic antagonists of possible interest in the field of Alzheimer's disease.

Synthesis and antiproliferative activity of some N-sulphonated-2-substituted benzimidazoles and imidazo[4,5-b]pyridines.

Some N-sulphonated-2-substituted benzimidazoles and imidazo[4,5-b]-pyridines were synthesized and tested in vitro for antiviral and antiproliferative activity. None of the compounds had antiviral properties. However, three of them inhibited the proliferation of leukaemia and lymphoma cell lines at micromolar concentrations. The maximum potency of antiproliferative activity is correlated with the presence of an ethylenic spacer between the two heterocycles.

Synthesis and antimicrobial activity of N, N-dialkyl-2-substituted-5-diazo-imidazole-4-carboxamides.

A series of 2-substituted-5-diazoimidazole-4-carboxamides has been synthesized, and their antimicrobial activity has been tested in vitro. Some of the compounds show antifungal activity related to the presence of small groups on the 4-carbox-amido moiety, while the presence of substituents in position 2 was detrimental.

Nonsteroidal antiinflammatory agents. XXIII. Synthesis and activity of stereomeric (+/-)-erythro- and (+/-)-threo-2-(4-biphenylyl)-3-hydroxy-2-methyl-3-phenyl-propionic acids.

In pursuing our research on the NSAIDs, the diastereomeric (+/-)-erythro- and (+/-)-threo-2-(4-biphenylyl)-3-hydroxy-2-methyl-3-phenyl-propionic acids (4 and 5) were synthesized; the last was also resolved in its optical isomers (6 and 7). The attribution of the relative configuration to 4 and 5 was performed by means of X-ray analysis. The compounds were tested for their antiinflammatory activity. The acid 4, which resulted very interesting, was tested also for analgesic and antipyretic activity, as well as for behavioural effects, gastric tolerability and acute toxicity. On the basis of the obtained data, this compound resulted a very promising one.

Some new quinoline-based mono and dicarboxylic acids.

Some quinoline-based mono- and dicarboxylic acids structurally related to kynurenic acid have been synthesized and screened as antagonists of neurotransmission of NMDA, AMPA and KA excitatory amino acid receptors. Higher affinity for NMDA receptor was pointed out in the short series, but all the compounds, even those with key structural features of glutamic acid showed no significant activity.

Nonsteroidal antiinflammatory agents. Part 21: optically active stereoisomers of p-trifluoromethylphenyl- and p-thioanisyl-biphenylyl- hydroxypropionic acids.

The synthesis, diastereomeric separation, assignment to erythro- and threo-configuration by 1HNMR, and optical resolution of 3-(p-trifluoromethyl-phenyl)- and (p-thioanisyl)-2-biphenylyl-3-hydroxypropionic acids are described. The enantiomers were submitted to a preliminary assay to determine antiinflammatory activity.

[Non-steroidal anti-inflammatory agents. XXII. Chiral aryl-hydroxy-fluorenylpropionic acids]. / Antiinfiammatori non steroidei. XXII--Acidi aril-idrossi-fluorenilpropionici chirali.

As fluorenyl rigid analogues of previous biphenylyl alcanoic acids with very interesting antiinflammatory activity, the 3-(m-tolyl and m-anisyl)-3-hydroxy-3-(2-fluorenyl)-propionic acids have been prepared by means of the Reformatsky reaction and following hydrolysis of the obtained ethyl esters. The preliminary antiinflammatory assay showed that the structural modification inactivates the compounds.

Nonsteroidal antiinflammatory agents. Part 20(3): Optically active thienyl-biphenylyl-hydroxypropionic acids.

The optically active diastereometric erythro- and threo-3-thienyl-analogues 6a-d of 3-aryl-2-biphenylyl-3-hydroxy-propionic acids have been prepared. Some stereoisomers of 3-(3-thienyl)derivative 6b showed inhibition around 40% in the carrageenan-induced rat paw edema test.

Synthesis and antimicrobial activity of some new benzodifurans and phenanthrolines.

A short series of di-functionalized benzodifurans and phenanthrolines were synthesized for in vitro antimicrobial activity. Dicarboxaldehydes, chiefly those with a phenanthroline supporting moiety, proved to be most effective, showing significant fungal growth inhibition.

Nonsteroidal antiinflammatory agents. XVIII - Stereomeric optically active halogenophenyl-biphenylyl-hydroxypropionic acids.

The optically active stereomers of some 3-(fluoro-, chloro-, bromophenyl)-2-biphenylyl-3-hydroxypropionic acids were prepared and tested for antiinflammatory activity. Surprisingly, the four bromo-isomers were the most active ones, particularly in the threo configuration.

[Nonsteroidal anti-inflammatory agents. 19. Synthesis and activity of stereomeric phenylacetic homologues]. / Nichtsteroidale Entzündungshemmer. 19. Mitteilung: Synthese und Aktivität von stereomeren Phenylessigsäure-Arylhomologen.

The authors synthesized the title compounds as analogues of previously prepared potential antiphlogistic agents. Starting from appropriate carbonyl compound and alpha-metallated phenylacetic acid the diastereomeric racemate pairs were obtained; they were separated, attributed to erythro/threo-configuration by NMR and finally resolved. The potassium salts of the enantiomers were tested for analgesic and antiinflammatory activity, as well as for acute toxicity. Their action in the carrageenan test has been found to be stereoselective, but relatively poor or of briefly lastening.

Nonsteroidal anti-inflammatory agents. Part 17: Stereomeric o-, m-tolyl- and anisyl-biphenylyl-hydroxypropionic acids.

As a part of wider research project on chiral anti-inflammatory arylacanoic acids, the 3-(o- and m-)-(methyl and methoxy)-phenyl-2-biphenylyl-3-hydroxypropionic acids 3a-d were synthesized and resolved in their optically active erythro and threo stereomers, which were submitted to the carrageenan induced rat paw edema test. With respect to the p-isomers, only the threo p-methoxy substitution enhances the anti-inflammatory activity. Some conclusions on structure-activity relationship are discussed.

Synthesis and antimicrobial activity of some N-monosubstituted 2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamides.

A short series of N-monosubstituted (aryl, aminoacyl, dipeptidyl)-2-(2-aminothiazol-4-yl)-(Z) -2-methoxyiminoacetamides was synthesized and tested for antimicrobial activity. A few members showed a somewhat interesting inhibitory action against Cryptococcus neoformans (MIC = 150 micrograms/ml).

Acidity constants of sparingly water-soluble drugs from potentiometric determinations in aqueous dimethyl sulfoxide.

A brief analysis of the acid-base equilibria in pure organic solvents and/or in their aqueous mixtures is reported with the aim of determining dissociation constants of acidic drugs that are sparingly soluble in water. Among aqueous organic mixtures, aqueous Me2SO (80% w/w) presents properties particularly suitable for acid-base studies, and thermodynamically meaningful acidity constants can be obtained by a potentiometric technique, provided that the glass electrode is properly calibrated. Thermodynamic acidity constants of more than 100 acids have been potentiometrically determined at 25 degrees C in this mixed solvent, and the selected series of acids has been divided into four classes according to the nature of the acidic group (COOH, OH, SH) and the structure of the acid (aliphatic, aromatic, heterocyclic). A linear relationship between the experimental pKa values in water and pKa values in aqueous Me2SO (80% w/w) has been found within the single classes and a group of equations has been derived (the asterisk denotes pKa values in which infinite dilution in the mixed solvent is taken as a standard state). For the carboxylic acid class, the following "common" equation has been found: pKa(H2O) = -0.80 + 0.67 pKa (Me2SO; 80% w/w). As an application, pKa values in water are reported for a representative number of sparingly soluble acids. These values have been calculated by means of the "common" equation, using pKa values experimentally determined in aqueous Me2SO (80% w/w). The calculated values are in good agreement with those expected from the acid structures.

Nonsteroidal antiinflammatory agents. Part 16: Stereomeric 3-aryl-biphenylyl-hydroxy-propionic acids.

As part of a wider research project on structure-activity relationships of chiral arylalkanoic acids, stereomeric aryl- biphenylyl-hydroxypropionic acids 3a-d have been prepared and their antiinflammatory activity evaluated. Diastereomeric racemic erythro- and threo-acids have been synthesized by reaction of alpha-lithiated biphenylyl-acetic acid salts with the appropriate aldehyde. They were separated, and after attribution of their relative configuration by 1H-NMR analysis, resolved. The antiinflammatory activities of the enantiomeric potassium salts were determined by the carrageenan test.