Physicochemical Substituent Parameters Research Articles

Quantitative structure-activity studies on indole alkaloid tumor promoter indolactam congeners

Nine indolactam congeners with L-Abu, gamma,delta-delta-Nva, Nva, Phg, tert-Leu, Leu, Ile, allo-Ile, Nle, instead of L-Val in (--)-indolactam-Val, were synthesized by microbial conversion and examined using two biological tests related to tumor promotion. The tests were inhibition of the specific binding of [3H]12-O-tetradecanoylphorbol-13-acetate (TPA) to the mouse epidermal particulate fraction, and stimulation of radioactive inorganic phosphate incorporation into phospholipids of HeLa cells. These two biological activities correlated well for each derivative. (--)-Indolactam-Ile with L-Ile in place of L-Val in (--)-indolactam-Val, which we have recently confirmed to occur naturally, was the most active of the ten indolactam congeners tested, suggesting that (--)-indolactam-Ile is a more potent tumor promoter than (--)-indolactam-Val in vivo. The effects of the substituents at position 12 on the TPA receptor binding were analyzed quantitatively using physicochemical substituent parameters and regression analysis. The results indicated that both hydrophobicity and bulkiness of the substituents at position 12 increased the binding ability to the TPA receptor, supporting the recent hypothesis that the isopropyl group at position 12 of (--)-indolactam-Val is involved in the hydrophobic interaction on the receptor site.

Quantitative analysis of uncoupling activity of substituted phenols with a physicochemical substituent and molecular parameters

The uncoupling potency of a series of substituted phenols with rat-liver mitochondria was analyzed quantitatively with physiochemical substituent and molecular parameters such as log P, P being the partition coefficient in a phosphatidylcholine liposome/water system, log K A , K A being the acid dissociation constant, and the Taft-Kutter-Hansch steric constant, E s, for ortho-substituents. The potency evaluated from the concentration in the medium required for a defined response was analyzed, showing that the incorporation of compounds in terms of log P, a certain balance between neutral and ionized forms expressible by a parabolic function of log K A and the steric shielding effect of the ortho-substituents on the negatively charged center of ionized form are highly significant factors governing the variations in potency. The potency was also quantitatively separated into the intrinsic potency as the protonophore inside the inner mitochondrial membrane and the incorporation factor in terms of log P. Some phenols found as outliers from the correlations and some others distorting the quality of the correlations were shown to have inhibitory effects on the respiratory chain by specific and non-specific modes of action, respectively, besides uncoupling activity.

Hydrophobicity Parameter of Diazines (1) Analysis and Prediction of Partition Coefficients of Monosubstituted Diazines

AbstractThe octanol/water partition coefficient (P) of a number of monosubstituted diazines was measured. The composition of the π value of substituents, the increment in the logP value accompanied with the introduction of substituents, was examined in terms of physicochemical substituent parameters and correlation analysis. The diazine‐π value of substituents was generally higher than the pyridine‐π value of corresponding substituents, indicating that the intramolecular electronic interactions between the ring‐N atoms and substituent are more pronounced than those in substituted pyridines in governing the logP value of the molecule. Except for 2‐substituted pyrimidines, the π value of substituents in each series of monosubstituted diazines was in general nicely correlated with the π value of the corresponding substituents in substituted pyridines along with electronic parameter terms representing “bidirectional” electronic effects on the relative solvation of the ring‐N atom(s) and the hydrogen‐bondable substituents with partitioning solvents according to the procedure proposed previously for the analysis of the π value in disubstituted benzenes and monosubstituted pyridines. Keeping in mind that 2‐pyrimidines substituted by hydrogen‐bondable groups sometimes behave as outliers, the correlations were believed to be usable for prediction of logP value of monosubstituted diazines.

Quantitative structure-activity relationships of the fungicidal methyl N-phenylcarbamates

For 69 methyl N-phenylcarbamates having various benzene ring substituents, the fungicidal activity was determined against Botrytis cinerea resistant to benzimidazole fungicides by the agar medium dilution method. The structure-activity relationships were analyzed quantitatively using such physicochemical substituent parameters as hydrophobic π, steric B 5, and HB (hydrogen bonding) with the Hansch-Fujita method (C. Hansch and T. Fujita, J. Amer. Chem. Soc. 86, 1616 1964). The hydrophobicity of substituents was favorable to the acitivity. The effect was position-specific, the importance being in the order of ortho ≅ meta > para. The activity was related parabolically to the maximum width of one of the m-substituents having the larger dimension. The hydrogen acceptability of p-substituents enhanced the activity. The preventive activity of compounds against gray mold of cucumber caused by the resistant B. cinerea, which was determined by the foliar application in pot tests, was dependent on the magnitude of the fungicidal activity and hydrophobicity of the compounds as analyzed by the adaptive least-squares method.

Quantitative structure—Activity studies of benzoylphenylurea larvicides: V. Substituted pyridyloxyphenyl and related derivatives

The larvicidal activity of analogs of a recently developed larvicide, chlorfluazuron, without 3,5-dichloro substituents at the phenyl moiety, i.e., of 2,6-difluorobenzoyl-4-(substituted 2-pyridyloxy)phenylurea, was estimated against the rice stem borer, Chilo suppressalis, under conditions in which oxidative metabolism was eliminated by the use of piperonyl butoxide. Results were analyzed quantitatively by physicochemical substituent parameters and regression analysis. The activity of some newly synthesized 2,6-difluorobenzoyl-4-substituted phenylureas with substituents at the para position that are electron-withdrawing, hydrophobic, and thin, such as Ph(4-Br). O(CH 2) 3Ph, and (Z)CHCHPh, were also measured against C. suppressalis and analyzed quantitatively. The results indicated that structural requirements for the activity of the whole series of compounds were basically identical with those for 2,6-difluorobenzoylphenylurea derivatives with simpler substituents.

Novel phenoxyalkylamine derivatives. V. Synthesis, alpha-blocking activity and quantitative structure-activity analysis of alpha-[(phenoxyethylamino)propyl]-alpha-phenylacetonitrile derivatives.

α-[(Phenoxyethylamino) propyy]-α-phenylacetonitrile derivatives possessing various substituents on the benzene ring (A ring) at the phenylacetonitrile moiety, on the quaternary carbon atom and on the benzene ring (B ring) at the phenoxy moiety, and exhibiting various degrees of ablocking activity, were prepared. The variations in the activity were analyzed qualitatively as well as quantitatively by using physicochemical substituent parameters and a regression technique. The effect of substituents on the A ring was rationalized in terms of a parabolic function of their hydrophobic parameter. As regards substituents on the quaternary carbon atom, alkyl groups were desirable for high activity. The effects of substituents on the B ring were such that an optimum hydrophobic condition exists and that an alkoxy substituent at the o-position as well as smaller substituents at the m-and p-positions are favorable for high activity. The analysis for the combined series of analogs where substituents on the A and B rings are varied showed the existence of an optimum hydrophobicity for the whole molecule for the transport process of the molecule, besides above-mentioned various position-specific structural effects.

Novel phenoxyalkylamine derivatives. IV. Synthesis, Ca2+-antagonistic activity and quantitative structure-activity analysis of alpha-isopropyl-alpha-[3-[3-(3-methoxyphenoxy)propylamino]propyl]- alpha-phenylacetonitrile derivatives.

α-Isopropyl-α-[3-[3-(3-methoxyphenoxy) propylamino] propyl] -α-phenylacetonitrile derivatives containing various substituents on the benzene ring (A ring) at the phenylacetonitrile moiety were prepared, and their Ca2+-antagonistic activity was evaluated. Among these compounds, the N-Me derivatives with m-OMe, p-F, p-Cl, 3, 4-(OMe) 2 and 3, 5-(OMe) 2 substituents on the A ring were found to show higher Ca2+-antagonistic activity than verapamil. The effect of substituents on the A ring was examined quantitatively using physicochemical substituent parameters and regression analysis. The analysis showed that substituents with a π value close to zero are favorable to the activity and that optimum steric conditions exist for m-and p-substituents, corresponding to those of m-OMe and p-F or p-Cl. The analysis for the whole series of analogs where substituents on the A ring, the benzene ring (B ring) at the phenoxy moiety and the quaternary carbon atom are simultaneously varied suggested that there is an optimum molecular hydrophobicity, perhaps participating in the transport process to the site of action, besides position-specific steric and hydrophobic effects.

Quantitative structure-activity studies of pyrethroids: 10. Physicochemical substituent effects of substituted benzyl pyrethrates on symptomatic and neurophysiological activities

The lethal and convulsive activities against American cockroaches and the knockdown activity against house flies of meta-substituted benzyl (1 R)- trans-pyrethrates and related compounds were measured under conditions where metabolic factors were minimized. The neuroexcitatory and blocking activities in central nerve preparations from the cockroaches were also measured with an extracellular recording technique. Variations in these activities were analyzed quantitatively by use of physicochemical substituent parameters and regression analysis, and the results were compared with those obtained from substituted benzyl (1 R)- trans-chrysanthemates. The most important parameters that governed these activities of the pyrethrates were hydrophobicity and the steric dimensions represented by the STERIMOL width and length of the aromatic substituents. The result was similar to that of the chrysanthemates. The relationships between the whole-body toxicities and the neurophysiological activities were also analyzed quantitatively. The cockroach toxicities could be analyzed by the neuroblocking activity index when the transport factor was separated by use of the hydrophobicity parameter. The house fly knockdown activity could also be analyzed in this way, but both neurophysiological activity indices were needed in the analysis.

Structure-activity studies of the indole alkaloid tumor promoter teleocidins

Abstract New teleocidin derivatives with various substituents at positions 2, 5 and 7 of the indole ring were prepared from (—)-indolactam V, which is the fundamental structure of teleocidins and has a tumor-promoting activity, to examine the contribution of the alkyl substituents of teleocidins to the activity. Their possible tumor-promoting activities in vivo were evaluated by Epstein—Barr virus early antigen-inducing activity and inhibition of specific binding of [3H]TPA to a mouse epidermal particulate fraction. These two biological activities correlated well for each derivative. Large substituents at positions 2 and 5 remarkably lowered the activities, indicating that the structural requirements for the activities of these domains are especially strict. To investigate in detail the contribution of position 2 of (—)-indolactam V to the activities, new microbial metabolites, (—)-2-oxy-indolactam V, and blastmycetin B and C, were also tested. These compounds proved to be inactive, suggesting that the double bond at position 2 plays an important role for the activities. Substituents at position 7 generally enhanced the activities and even blastmycetin A, which is a dimer of (—)-indolactam V, showed high activities. The effects of the substituents on binding ability to the 12-O-tetradecanoylphorbol-13-acetate receptor were analyzed quantitatively using physicochemical substituent parameters and regression analysis. The results exhibited the fact that hydrophobicity of the substituents plays a critical role for receptor binding, and supported the hypothesis that the monoterpenoid moiety of teleocidins is involved in the non-specific hydrophobic interaction with phospholipids in cell membrane.

Quantitative structure-activity studies of substituted benzyl chrysanthemates: 6. Physicochemical properties and the susceptibility to metabolic degradation in American cockroaches

For a series of substituted benzyl chrysanthemates and their dichlorovinyl-sidechain (permethrin) analogs, indices of the in vivo metabolic susceptibility to oxidative and hydrolytic degradation were defined and estimated from insecticidal activities against male adult American cockroaches measured under nonsynergistic and synergistic conditions. Piperonyl butoxide was used as the synergist inhibiting oxidative degradation and NIA 16388 as that against hydrolytic metabolism. Hydrolytic degradability was also experimentally determined in vitro for permethrin analogs using an enzyme preparation from homogenates of the abdominal part of female adult American cockroaches. The effects of substituents of the alcohol moiety on these two types of metabolic parameters were analyzed in terms of physicochemical substituent parameters and regression techniques. Although a number of suggestions on the mechanisms of metabolism were derived from these analyses, the factors determining the in vivo metabolic susceptibility do not always correspond with those participating in the in vitro metabolism. The in vivo metabolic parameter is that comparing the metabolic degradability under conditions in which they exhibit a specified potency of insecticidal activity, differing from the in vitro “absolute” degradability.

Quantitative structure-activity studies of benzoylphenylurea larvicides: II. Effect of benzyloxy substituents at aniline moiety against Chilo suppressalis Walker

The larvicidal activity of a series of N-2,6-difluorobenzoyl- N′-[4-(substituted benzyloxy)-phenyl]-ureas against nondiapause larvae of the rice stem borer, Chilo suppressalis Walker, was measured by a topical application method under conditions in which oxidative metabolism was inhibited by piperonyl butoxide. The effects of the substituted-benzyloxy moiety on variations in the activity were analyzed quantitatively using physicochemical substituent parameters and regression analysis. Results were compared with those found previously for N-2,6-difluorobenzoyl- N′-(4-substituted phenyl)-ureas, indicating that the electron-withdrawing property of the anilide substituents participates in determining the activity through the inductive effect. The hydrophobicity of the total anilide substituents favors activity, whereas the steric dimension in terms of the width lowers it. Although inhibition of new cuticle formation on cultured integument of diapausing larva could not be determined accurately for most of the compounds because of their limited solubility in the assay medium, inhibitory activity seemed related to larvicidal activity, as was the case for previously investigated simpler congeners.

Quantitative structure-activity studies of benzoylphenylurea larvicides: I. Effect of substituents at aniline moiety against Chilo suppressalis walker

The larvicidal activity of a series of N-2,6-difluoro- and N-2,6-dichlorobenzoyl- N′-(4-substituted phenyl)ureas against nondiapause larvae of the rice stem borer, Chilo suppressalis Walker, was measured by topical application and oral administration methods under conditions with and without piperonyl butoxide as an inhibitor of oxidative metabolism. The effects of substituents at the anilide moiety on the larvicidal activity were analyzed quantitatively using physicochemical substituent parameters and regression analysis. The results indicate that the oxidative metabolism in the larval body which is favored by electron-donating substituents is significant in determining the activity. The activity, when the metabolic factor is eliminated, is enhanced by electron-with-drawing and hydrophobic substituents and lowered by bulky groups. The inhibitory activity against new cuticle formation of the same series of compounds was also measured using cultured integument of the rice stem borer diapause larva. The comparison of the quantitative analyses between larvicidal and integument-level activities shows that inhibition of cuticular development is the most important factor governing larvicidal activity.

Competitive binding to the cytosolic 2,3,7,8-tetrachlorodibenzo- p-dioxin receptor : Effects of structure on the affinities of substituted halogenated biphenyls—A QSAR analysis

The proposed mechanism of action of the toxic halogenated aromatics, typified by 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD), involves the initial binding to a high-affinity, low-capacity, cytosolic receptor protein. Previous studies have shown that several 4'-halo-2,3,4,5-tetrachlorobiphenyls bind to the TCDD receptor and that a lateral substituent on both phenyl rings is required for activity. Using an extended series of eighteen 4'-substituted-2,3,4,5-tetrachlorobiphenyls as probes, the effects of a variable lateral substituent on receptor binding affinity and the induction of aryl hydrocarbon hydroxylase (AHH) in vivo and in rat hepatoma H-4-II E cells have been determined. For most substituents, there was an excellent correlation between the rank-order potency for receptor binding and the rank-order potency for AHH induction. Based on in vitro binding affinities ( ec 50 values) of the 4'-substituted tetrachlorobiphenyls, a multiparameter regression equation was formulated correlating the binding constants to physicochemical substituent parameters. For thirteen compounds out of the present series, multiple regression analysis of the binding data led to the following equation: log(1/ ec 50) = 1.530σ + 1.47π + 1.09HB + 4.08, r = 0.978. The results suggest that halogen substitution on both phenyl rings is not a requirement for binding and that hydrophobic (π) and electronic (σ) substituent constants and a variable for hydrogen bond (HB) formation are significant parameters describing relative binding avidities of this series of substituted biphenyls for the TCDD receptor.

Quantitative structure-activity studies of substituted benzyl chrysanthemates: 3. Physicochemical substituent effects and the spontaneous neuroexcitatory activity on the crayfish abdominal nerve cords

Neuroexcitatory activity of a series of m- and p-substituted benzyl (1 R)- trans-chrysanthemates was determined using the abdominal nerve cords excised from crayfishes, in terms of the concentration required to increase the spontaneous discharge frequency to a certain value, as well as the rate of the increase of the discharge frequency. The indices for these two types of activity were analyzed quantitatively by means of physicochemical substituent parameters and regression analysis. Being determined most significantly by the steric volume effect, the equineuroexcitatory concentration was found to vary according to the position-specific substituent effects which are very similar to those observed for the neuroexcitatory activity on nerve cords of American cockroaches. The rate of the frequency increase, which is supposed to reflect the rate of penetration into the nerve tissue, was shown to be enhanced by the hydrophilic as well as the electron-withdrawing substituents.

Quantitative structure-activity relationships (QSAR) with variable contribution of substituents to the biological activity of chemical compounds

of each of the i-substituents x i in each of the j-positions of the paren t structures, and is widely used for detecting quantitative structure--activity relationships, particularly in those cases when for some reason, reliable values for physicochemical substituent parameters such as the Hansch hydrophobic constant ~, the Taft constant Es, or the Hammett g are impossible i to obtain from the materials under study. In Eq. (i) the contribution to the biological activity of each substituent group in each position is assumed to be constant in value and in sign, and not dependent on either the presence or the structure of other substituent groups in other positions of the parent molecule.

Quantitative structure-activity relationship of cytokinin-active adenine and urea derivatives

Abstract The substituent effect of N 6 -alkyl and -aralkyl adenines on the promotion of the growth of tobacco callus was analysed quantitatively using physico-chemical substituent parameters and regression analysis. The results indicated an optimum steric condition for activity in terms of the maximum width of the N 6 -substituents from the bond-axis connecting the N 6 -atom with its α carbon atom. The electron withdrawing effect of the N 6 -substituent enhances the activity. The substituent effect on the cytokinin activity of phenyl- and diphenyl- urea derivatives determined by Bruce and Zwar using the tobacco pith-block assay was also analysed. The results suggest that position-specific steric and hydrophobic effects of aromatic substituents participate in the variation in activity rationalizing the general trend of the activity; meta > para > ortho derivatives, for both series of compounds. The electronic effect is significant for the activity of diphenylureas but not for that of phenylureas which show somewhat different modes of interaction between the two series at the site of action. Based on inferences made from the correlations, hypothetical maps for the mode of interaction of these three sets of compounds at the site of action have been proposed.

Quantitative structure-activity relationships of antifungal N-phenylsuccinimides and N-phenyl-1,2-dimethylcyclopropanedicarboximides

The antifungal activity of 61 N-phenylsuccinimides and 16 N-phenyl-1,2-dimethylcyclopropanedicarboximides having various benzene ring substituents was determined against Botrytis cinerea by the agar medium dilution method. The structure-activity relationships were analyzed using such physicochemical substituent parameters as hydrophobic π, electronic σ 0, steric E 8, and HB (hydrogen bonding) values with the multiple regression technique. The π values were derived from log P (octanol-water partition coefficient) values for the N-monosubstituted-phenylsuccinimide system. The hydrophobic effect is significant only for m-substitutents. The stronger the electron withdrawal and the smaller the steric dimensions of the ring substituents, the greater is the activity. When substituents are hydrogen bond acceptors, the effect is to lower the activity. These features are almost identical between two series of compounds.

Quantitative analysis of anticytokinin activity of 4-substituted-2-methylthiopyrido[2,3- d]pyrimidines

Ten 4-substituted-2-methylthiopyrido[2,3- d]pyrimidines were synthesized and tested for their cytokinin-antagonistic activity by the tobacco callus bioassay. This series of compounds constitutes the first example of anti-cytokinins which possess a fused 6-6 membered ring system. The treatment of Lineweaver and Burk, the method of classical enzyme kinetics, revealed competitive inhibition of cytokinin-induced tobacco callus growth. The variation of activity with the systematic transformation of 4-substituents was analysed quantitatively with physicochemical substituent parameters and regression analysis. The results indicated the predominant importance of substituent width for binding of the antagonists at the receptor site of cytokinins.

Structure-activity study of beta-adrenergic agents using the SIMCA method of pattern recognition.

The SIMCA method of pattern recognition (PaRC) was used to analyze structure-activity data for a series of phenethylamine agonists and antagonists of the beta-adrenergic receptor. On the basis of physicochemical substituent parameters the SIMCA method classified correctly 100% of the agonists and 88% of the antagonists. In addition, parameters derived from the class models were correlated with the biological activities of the agonists and antagonists, respectively. Test compounds not included in the initial data analysis were classified and their activities estimated. The applicability of pattern recognition in structure-activity studies in general is discussed.

Structure-activity relationship of lindane analogs

With 38 lindane analogs in which some of the chlorine atoms are replaced by other substituents, the relationship between structure and insecticidal activity on mosquitos ( Culex pipiens pallens) was analyzed by means of physicochemical substituent parameters and regression analysis. A sufficient hydrophobicity as well as a sufficient stability for spontaneous decomposition in vivo appeared to be indispensable to the activity. For analogs satisfying these conditions, the relative insecticidal activity was determined by steric effects of substituents in a manner highly specific to their positions in the molecule. In order to exhibit potent activity, the analogs were assumed to fit a hypothetical cavity wall at the critical site of action with a proper contact at the meso-positions as well as with a suitable engulfment at the dl-positions. Remarkably, the meso-Br analogs are 1.5–2 times more active than lindane. Substituents other than Cl at the dl-positions generally reduce the activity.