Quantitative Structure-activity Studies Research Articles

Quantitative structure-activity studies of substituted benzyl chrysanthemates: 1. Correlations between symptomatic and neurophysiological activities against American cockroaches

A number of substituted benzyl (1R)-trans-chrysanthemates and related compounds were synthesized. Their symptomatic activities in terms of levels which induce convulsions as well as cause death in American cockroaches were determined by injection with and without application of synergists as inhibitors of metabolism. The neuroexcitatory and neuroblocking activities were also determined in terms of minimum effective concentrations to induce repetitive train of impulses and conduction blockage, respectively, to central nerve cords excised from the cockroaches and immersed in Ringer's solution. Correlations between symptomatic and neurophysiological activities were analyzed quantitatively with the aid of molecular hydrophobicity parameter and regression analysis. Each symptomatic activity from which the effect of metabolism is eliminated was found to be analyzable by means of a linear combination of indices for two types of neurophysiological activity when the transport factor is separated by using the hydrophobicity parameter. A closer correlation was found between neuroblocking activity and the “convulsive” effect than between neuroexcitatory activity and the “convulsive” effect, whereas both neurophysiological effects operate together on the cockroaches resulting in paralysis and death.

A quantitative structure-activity study of anticonvulsant benzyl N,N-dimethylcarbamates.

A series of m-and p-substituted benzyl N, N-dimethylcarbamates was prepared then evaluated for anticonvulsant activity in mice by means of the maximal electroshock seizure test. The ED50 value correlated well with the hydrophobic (log P, 1-octanol-H2O partition coefficient), electronic (σ°) and hydrogen bonding (HB) characters of the tested compounds on regression analyses. The relative activity depended parabolically on log P ; the optimum value of hydrophobic character (log P0) was 1.82. This agrees well with values found empirically for central nervous system depressants (log P0≃2). Electron-donating substituents enhanced the activity, an indication of interaction between the carbamoyl moiety and an acidic group on the receptor site. Hydrogen bond-accepting ability of the substituent reduced anticonvulsant activity, while non-hydrogen bonders did not. The overall substituent effects were such that the activity of the unsubstituted compound was almost optimum.

ChemInform Abstract: STRUCTURE‐ACTIVITY RELATIONSHIPS OF ANTIBACTERIAL 6,7‐ AND 7,8‐DISUBSTITUTED 1‐ALKYL‐1,4‐DIHYDRO‐4‐OXOQUINOLINE‐3‐CARBOXYLIC ACIDS

AbstractAus den Anilinen (I) erhält man mit dem Malonsäureester (II) die Enamine (III), die thermisch zu den Chinolinen (IV) cyclisiert werden.

Structure-activity relationships of antibacterial 6,7- and 7,8-disubstituted 1-alkyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acids.

Previous quantitative and qualitative structure-activity studies in antibacterial monosubstituted 1-ethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acids prompted us to synthesize the 6,7,8-polysubstituted compounds. In this paper, the preparation and antibacterial activity of the 6,7- and 7,8-disubstituted compounds and their derivatives are described. Among these compounds, 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)quinoline-3-carboxylic acid (34) possessed many significant activities and was more active than oxolinic acid (84) against Gram-positive and Gram-negative bacteria. Structure-activity relationships are discussed.

Quantitative structure-activity study of herbicidal N-aryl-3,4,5,6-tetrahydrophthalimides and related cyclic imides

The quantitative relationship between structure and inhibitory activity against the root growth of sawa millet of 30 N-aryl-3,4,5,6-tetrahydrophthalimides and 88 related N-aryl cyclic imide compounds (3-aryl-1,5-tetramethylenehydantoins, 4-aryl-1,2-tetramethylenetriazolidine-3,5-diones, and their thiocarbonyl analogs) was analyzed by means of physicochemical parameters of the aryl substituents and regression analysis. The results showed that, in each series of these classes of compounds, the position-specific steric effects of aromatic substituents, as represented by Verloop's STERIMOL values, are highly important in determining the inhibitory potency of the compound.

Inhibition of chlorphentermine binding in rat lung: Application of connectivity theory

Using the recently developed theory of molecular connectivity, the structural requirements of compounds inhibiting the binding of chlorphentermine in rat lung were examined. Only two indices, 4χ p ν and 7χ p ν , were necessary to adequately describe the activity of the set of compounds considered. Further analysis of the factors determining the values of the indices revealed that the magnitude of each index was directly related to the number of pathways and inversely related to the atomic valencies constituting the indices. The relative number of pathways was found to be a function of the degree of cyclisation and substitution on or near the cyclic substructures. The effect of atomic valencies on index values was conveniently examined by introducing an ‘average valence’ term i δ p ν . It was concluded firstly that inhibition of chlorphentermine binding in rat lung was greatest for multicyclic compounds with low valence atoms substituted on or near the ring substructures, and secondly that the ability of the connectivity theory to define the activity of a relatively non-homogeneous data set indicates its potential in quantitative structure-activity studies.

Quantitative structure–activity study of some enzyme‐inhibitory quinazolines

AbstractRelationships are formulated to explain the variation in dihydrofolate reductase inhibitory potency for a series of 25 substituted quinazolines, with an antineoplastic potential. Highly significant correlations are obtained using CNDO/2–3R calculated indices and/or the empirically estimated molecular polarizability as independent variables. The MO calculated indices employed are the atomic polarizability, as defined herein, and bond energy. The molecular polarizability is represented by a simple sum of environment independent partial atomic polarizabilities. The partial polarizabilities, reported here for H, C, N, O, F, S, Cl, and Br, are obtained from a multiple regression forced through the origin.

ChemInform Abstract: AMES TEST OF 1‐(X‐PHENYL)‐3,3‐DIALKYLTRIAZENES. A QUANTITATIVE STRUCTURE‐ACTIVITY STUDY

Chemischer InformationsdienstVolume 10, Issue 40 Other Subjects ChemInform Abstract: AMES TEST OF 1-(X-PHENYL)-3,3-DIALKYLTRIAZENES. A QUANTITATIVE STRUCTURE-ACTIVITY STUDY B. H. VENGER, B. H. VENGERSearch for more papers by this authorC. HANSCH, C. HANSCHSearch for more papers by this authorG. J. HATHEWAY, G. J. HATHEWAYSearch for more papers by this authorY. U. AMREIN, Y. U. AMREINSearch for more papers by this author B. H. VENGER, B. H. VENGERSearch for more papers by this authorC. HANSCH, C. HANSCHSearch for more papers by this authorG. J. HATHEWAY, G. J. HATHEWAYSearch for more papers by this authorY. U. AMREIN, Y. U. AMREINSearch for more papers by this author First published: October 2, 1979 https://doi.org/10.1002/chin.197940332Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume10, Issue40October 2, 1979 RelatedInformation

Stimulated production of slow reacting substances by mercaptans from ionophore A 23187- induced mononuclear cells: Mercaptan structure-activity studies

When isolated mononuclear cells from the peritoneal cavity of the rat are challenged with the ionophore, A 23187, slow reacting substance (SRS) is produced. SRS production is markedly enhanced by the addition of mercaptans to the incubations. In confirmation of previously published reports, this enhancement is dependent on the duration of a preincubation of the cells with the mercaptans before addition of the ionophore, a two minute preincubation being optimal. Quantitative structure-activity studies revealed that a variety of mercapto carboxylic acids, where the mercapto group was one or two carbon atoms removed from the carboxyl group, were all active in enhancing SRS production and the enhancement followed parallel dose response curves. A 4-mercapto acid, while weakly active, had a distinctly different dose response curve and cysteamine, which lacks a carboxyl function, was inactive. Preliminary characterization of the products of the incubations produced in the presence of different mercaptans has revealed that, while they all qualitatively meet the criteria of stability to alkali, lability in acid and destruction by arylsulfatase which are associated with slow reacting substance of anaphylaxis, there are quantitative differences in stability which suggest that the products may not be identical.

Quantitative structure activity study of a series of substituted 0,0-dimethyl 0-(p-nitrophenyl) phosphorothioates and 0-analogs

The lethality of seven 0,0-dimethyl 0-(p-nitrophenyl) phosphorothioates and their corresponding oxons has been determined in adult, male mice. The anticholinesterase potency of the oxons for bovine, erythrocyte acetylcholinesterase has also been determined. The LD50 values in mg/kg were: methylparathion, 33.1; fenitrothion, 988; chlorothion, 794; decapthon, 331, 0,0-dimethyl 0-(3 ethyl-4-nitrophenyl) phosphorothioate, 1396; 0,0-dimethyl 0-(3-isopropyl-4-nitrophenyl) phosphorothioate, 1379, and 0,0-dimethyl 0-(3,5-dimethyl-4-nitropenyl) phosphorothioate, 630. The lethality values for the 0-analogs were: methyl paraoxon, 21.8; fenitrooxon, 120; chloroxon, 280; dicapthoxon, 102; dimethyl-3-ethyl-4-nitrophenyl phosphate, 191; dimethyl-3-isopropyl-4-nitrophenyl phosphate, 321; dimethyl-3,5-dimethyl-4-nitrophenyl phosphate, 630. The pI50 values for inhibition of bovine red blood cell cholinesterase by the oxons were: methyl paraoxon, 7.2; fenitrooxon, 6.2; chlorooxon, 7.0; dicapthoxon, 7.1; dimethyl-3-ethyl-4-nitrophenyl phosphate, 6.0; dimethyl-3-isopropyl-4-nitrophenyl phosphate, 6.0; and dimethyl-3,5-dimethyl-4-nitrophenyl phosphate, 5.4. All the substitutions on the 4-nitrophenyl nucleus decreased toxicity whereas conversion of the phosphorothioates to oxons increased toxicity. The substituted oxons were all less toxic than methyl paraoxon while the substituted phosphorothioates were all less toxic than methyl parathion.

Hydrogen-bonding parameter and its significance in quantitative structure--activity studies.

When the relative hydrogen-bonding effect of drugs on phases involved in the binding at the site of biological action differs from that in the 1-octanol-H2O partitioning phases used as the reference to estimate the hydrophobicity, a parameter (or parameters) which represents the "extra" hydrogen-bonding effect on the biological activity is required in the Hansch-type correlations. As a first approximation, the effect is analyzed in terms of the ratio of hydrogen-bonding association constants and the ratio of molarities of hydrogen-bonding species constituting the biological and organic phases. Sometimes, the association constants in both phases are so similar that they are not important in determining the extra hydrogen-bonding effect. The net result is that the effect is expressible by an indicator variable term the slope of which corresponds to the molarity ratio. The variable only applies to substituents having appreciable association capability in correlating a certain biological action exhibited by a series of congeners.

Thyroxine analogs. 23. Quantitative structure-activity correlation studies of in vivo and in vitro thyromimetic activities

Quantitative structure-activity correlation studies of thyroid hormone analogues have been utilized to examine (1) in vivo rat antigoiter activities; (2) in vitro binding affinities to intact rat hepatic nuclei, solubilized rat hepatic nuclear protein receptors, and the plasma protein thyroxine binding globulin; and (3) correlations between in vivo antigoiter activities and in vitro binding to nuclear receptors. These studies provide a more precise elucidation of the relative importance of the physiochemical factors which influence thyromimetic activities. In particular, they (1) provide the first systematic QSAR examination of drug-receptor interactions and of the dependence of in vivo activity on such interactions; (2) demonstrate the importance of the interactive effects of the 3' and 5' substituents and of the 4'-OH with each other as well as with nuclear receptors in influencing binding affinity; (3) support the hypothesis that binding to nuclear receptors is the first step in initiating the events which lead to subsequent hormonal expression; (4) show that the free energy of binding to nuclear receptors can be factored into the contributing physicochemical properties of the substituents; and (5) suggest factors that need to be considered in designing new analogues.

Inhibition of Streptococcus faecalis by long chain aliphatic monoamines: quantitative structure-activity studies.

Primary, secondary, and tertiary long chain aliphatic amines were synthesized, and their activity against Streptococcus faecalis was determined. Quantitative structure-activity analyses were carried out based on the Hansch extrathermodynamic model, using partition coefficients, CMC's, quantum mechanical charges on the amine nitrogen, and the Taft steric parameter. The best correlations were obtained with the CMC. Steric properties of the ammonium head become important for tertiary amines. The structural feature of these compounds that dominates biological activity is the length of the alkyl tail. Ammonium head substituents are of only secondary importance.

Quantitative structure-activity studies on monoamine oxidase inhibitors.

Quantitative structure-activity studies were carried out on a series of N-isopropylaryl hydrazides which inhibits monoamine oxidase (MAO). The inhibitory potencies of these compounds of MAO were found to correlate with the electron-withdrawing capacity of the aryl ring substituents as estimated by both empirical Hammet sigma constants and electronic indices from molecular orbital calculations. Based on these correlations and previously published data on other classes of MAO inhibitors, a general model for the inhibitor pharmacophore is proposed: potent MAO of an aromatic ring; electron-withdrawing groups on the aromatic ring or replacing the phenyl ring with certain types of heterocyclic rings will tend to increase the potency.

Mode of action and quantitative structure-activity correlations of tuberculostatic drugs of the isonicotinic acid hydrazide type.

Quantitative structure-activity studies have been performed for a series of 2-substituted isonicotinic acid hydrazides by correlating electronic, steric, and lipophilic properties of the substituents with the biological activity date (MIC) from serial dilution tests with Mycobacterium tuberculosis (strain H 37 Rv). The reaction rates for the quaternization of 2-substituted pyridines with methyl iodide were also determined. The rate constants show a similar dependence on the steric and electronic effects of the substituents as the antibacterial activities of the corresponding pyridine-4-carboxylic acid hydrazides. The obtained correlations give evidence that the reactivity of the pyridine nitrogen atom is essential for the biological activity of 2-substituted isonicotinic acid hydrazides and seem to support the hypothesis that isonicotinic acid derivatives are incorporated into an NAD analogue.

Structure-activity correlations in a homologous series of 2-substituted isonicotinic acid hydrazides.

Quantitative multiparameter structure-activity studies have been performed on a series of 2-substituted isonicotinic acid hydrazides (Fig. 1). Isonicotinic acid hydrazide (INH) has been one of the most effective drugs in tuberculosis therapy since 1952 when its antibacterial activity against Mycobacterium tuberculosis was discovered [1, 2]. Numerous derivatives have been prepared since then, however, none of them possessed a higher activity than INH itself.

Quantitative structure-activity studies. I. Parameters relating to hydrophobicity.

The logarithm of partition coefficient between octanol and water, log P, widely used in structure-activity studies as a hydrophobic parameter was factored into two intrinsic components, free molecular volume and hydrophilic effect of polar group. Among those additive parameters relating to molecular volume as parachor, molar refraction, diamagnetic susceptibility, molar attraction constant, and Exner's molar volume, Quayle's atomic parachor, Pr, showed the best correlation with observed log P for apolar compounds. The hydrophilic group effect, Ew, was estimated as a correction term in the evaluation of log P for polar compounds by using a linear relation of log P to Pr obtained for apolar molecules. The parameters Pr and Ew could be satisfactorily applied to the regression analysis of water-solubility of 156 organic liquids and frog muscle narcosis of 39 drugs. These artificial parameters have a great advantage in drug design because they can be evaluated for a wide variety of classes of compounds before the molecules are even synthesized.

Mechanism of antimalarial activity of chloroquine analogs from quantitative structure-activity studies. Free energy related model.

Mechanism of antimalarial activity of chloroquine analogs from quantitative structure-activity studies. Free energy related model.