Lipophilic character of cardiac glycosides: correlation between RM values and acute toxicity data in different animal species.

The RM for a new series of cardiac glycosides were calculated by means of some of the delta RM values previously derived from another series of compounds. The experimental or calculated RM values of both series of derivatives were correlated with the acute toxicity data (log 1/C). The slopes of the linear equations for cats, dogs, guinea-pigs and frogs are very close, showing that the dependence of toxicity on the lipophilic character is the same in these animal species.

Study of the lipophilic character of a series of beta-carbolines.

The lipophilic character of a series of beta-carbolines has been studied. The RM values were measured by means of a reversed-phase thin-layer chromatographic (TLC) technique and compared with the RM values obtained by high-performance TLC (HPTLC), the log k' obtained by high-performance liquid chromatography (HPLC), and the log P values. The best equation shows a very good linear relationship between our RM values and the classical log P values obtained using an octanol-water system. The choice of a pH of 13.0 for the TLC system allowed the measurement of the RM values of molecules in their non-ionized form. The deviations from the linear relationship shown by the RM(HPTLC) and log k' values of two compounds were due to the fact that both compounds were at least partially ionized at the pH of 7.0 at which the HPTLC and HPLC determinations were carried out.

The influence of physicochemical parameters on the biliary excretion of a series of nitroimidazoles.

The relationship between physicochemical parameters and biliary excretion of nitroimidazoles was investigated. The unmetabolized form of each drug was detected in the bile by means of a UV procedure. A highly significant reversed parabolic relationship was shown between the Rm values and the biliary excretion of the test compounds. In other words, the compounds closer to the optimal Rm value are excreted less than those characterized by higher or lower Rm values. Since the Rm values seem to account for both the lipophilic and polar character of nitroimidazoles, the reversed parabola could be due to plasma protein binding and/or some protein binding within the hepatocyte. In fact, both the lipophilic and polar character seem to play an important role in protein binding of chemicals.

Relationship between lipophilic character and urinary excretion of nitroimidazoles and nitrothiazoles in rats.

Many processes are involved in the renal excretion of drugs, but very little is known about their quantitative structure-activity relationship. The relationship between urinary excretion and lipophilic character of a series of nitroimidazoles and nitrothiazoles was studied. The unmetabolized forms of the drugs were detected in the urine by means of UV and HPLC procedures. The urinary excretion of unmetabolized forms is parabolically related with the log P, as an expression of lipophilic character of molecules.

Structure-activity relationship of nitroimidazo (2,1-b) thiazoles in the Salmonella mutagenicity assay.

The mutagenic activity of a series of nitroimidazo (2,1-b) thiazoles was determined in Salmonella typhimurium TA-100 strain by means of the Ames test. A multiple regression analysis showed a highly significant parabolic relationship between mutagenic activity and the Rm values as an expression of the lipophilic character of molecules. The lipophilic character should be important in determining an optimal cell permeation. However when the lipophilic character was expressed by means of the sigma pi values the equation was much less satisfactory. This could be due to the fact that the Rm values of nitroheterocyclic compounds actually represent a measure both of lipophilic and polar character.

Quantitative relationship between structure and mutagenic activity in a series of 5-nitroimidazoles.

The mutagenic activity of 20 5-nitroimidazoles was tested in Salmonella typhimurium TA-100 strain by means of the Ames test. A multiple regression analysis using the interaction term MR2 X Hb and the chromatographic Rm values yielded the equation: (formula see text); where C is the molar concentration (1 M X 10(-6) of each drug increasing the revertants by five times in the Ames test. The interaction term MR2 X Hb takes into account the positive effect exerted by substituents characterized by higher molar refractivity (MR2) and capable of hydrogen bonding (Hb). It was found that when the electroreduction potentials (EIc.p.) were included, the correlation was not improved.

Mutagenicity of a series of 25 nitroimidazoles and two nitrothiazoles in Salmonella typhimurium.

Twenty-five 5-nitroimidazole and two 5-nitrothiazole derivatives were tested for mutagenicity as well as for antibacterial activity in Salmonella typhimurium TA-100 strain. Many of these compounds such as metronidazole, azanidazole, nimorazole, carnidazole, ornidazole, tinidazole, etc are extensively used in human chemotherapy, and some of them were recently synthetized for possible clinical trials as hypoxic cell specific radiosensitizers. Both mutagenic and antibacterial activity were shown for 22 of the test compounds. The high correlation between mutagenic and antibacterial activity supports the hypothesis of a same mechanism for both activities. The present results confirm that the mutagenicity of the nitroheterocyclic compounds is not separated from other biological activities, such as antimicrobial activity.

Rm values and structure-activity relationship of benzodiazepines.

Quantitative structure-activity relationships (QSAR) have been formulated for the activities of a series of benzodiazepines in rats. The lipophilic character of molecules was expressed by means of the chromatographic Rm values which were very well correlated with experimental or calculated log P values. The ideal lipophilic character for activity of benzodiazepines in the exploratory behavior test is not far from that of compounds acting in the central nervous system as unspecific depressant agents. The results of both the conflict and exploratory behavior studies might support the hypothesis of different sites of action for the antianxiety and sedative effects of benzodiazepines.

RM values of naphthols and acetophenones in structure-activity studies.

The RM values of naphthols obtained in a chromatographic system where the stationary phase consisted of a silica gel G layer impregnated with silicone oil are much more closely related to the log P values in an octanol-water system than the RM values determined on polyamide layers. Similarly, the RM values of a series of acetophenones in the silicone system are closely related to their log P values. The equations describing the structure-activity relationship indicate the importance of lipophilic character and halogen substitution in determining the hemolytic activity and the acute toxicity of compounds.

[Non-steroidal anti-inflammatory agents. VI. Optically active 3-(4-biphenylyl)-3-oxybutyric, valerianic, caproic and isocaproic acids]. / Antiinfiammatori non steroidei. Nota VI - Acidi 3-(4-bifenilil)-3-ossibutirrico, valerianico, capronico e isocapronico otticamente attivi.

The synthesis of the (+/-) 3-(4-biphenylyl)-3-hydroxybutanoic, pentanoic, hexanoic and isohexanoic acids, and their resolution in to enantiomers are described. The latter were submitted to preliminary assay for antiinflammatory activity: interesting results were obtained above all for the isohexanoic acid derivative.

[Non-steroidal anti-inflammatory agents. V. Optically active 4-biphenylyloxybutyric and 4-biphenylylglycolic acids]. / Antiinfiammatori non steroidei. Nota V - Acidi 4-bifenililossibutirrici e 4-bifenililglicolici otticamente attivi.

The synthesis and the resolution of the enantiomers of (+/-)2-(4-biphenylyl)-4-oxybutyric and (+/-)4-(4-biphenylyl)-2-oxybutyric acids and the resolution of the enantiomers of (+/-)2-(4-biphenylyl)-2-oxybutyric and (+/-)4-biphenylylglycolic acids are described. The potassium salts of each enantiomer were submitted to preliminary assays of antiphlogistic activity.

Antiinflammatory activity of four isomers of 2-(4-biphenylyl)-3-hydroxybutyric acid.

The degree of stereospecificity of the antiinflammatory activity of four isomers of 2-(4-biphenylyl)-3-hydroxybutyric acid was investigated in three different tests. The erythro compounds were the most active ones. As the "optical isomers effect" was not significant, this could indicate that the "diastereoisomer effect" is more important than optical isomerism.

Rm values of phenols. Their relationship with log P values and activity.

The experimental Rm values for a series of phenols were obtained by a reversed-phase TLC system. The extrapolation from a range of linear relationship between experimental Rm values and acetone concentration provided a set of extrapolated Rm values. This were used for studying the relationship between structure and activity in vitro and in vivo. The possibility to obtain by means of the extrapolation technique the Rm values in a standard system for serveral series of chemotherapeutic agents is pointed out.

Rm values of steroids as an expression of their lipophilic character in structure-activity studies.

The chromatographic Rm values of three series of steroids were determined by means of a reversed-phase system. The Rm values at 45% acetone in the mobile phase were shown to be correlated with the partition coefficients in an ether-water system. However, an almost equally good correlation was found when using extrapolated Rm values. The extrapolation technique could provide a standard system. The relationship between biological data and Rm values pointed out the important role of the lipophilic character in regulating the activity of steroids. In particular, the dependence of protein binding absorption and biotransformation on lipophilic character might strongly influence the availability of steroids at the site of action.