Quantitative Structure-activity Studies Research Articles

Structure-activity study of the interaction of bioreductive benzoquinone alkylating agents with DNA topoisomerase II

Quantitative structure-activity studies were performed on a series of benzoquinone mustard (BM) bifunctional alkylating agents to determine whether DNA topoisomerase II (topo II) inhibition was responsible for cell growth inhibition. Topo II inhibition was evaluated by decatenation and agarose gel electrophoresis assays. The BM compounds were shown to potently inhibit the decatenation activity of topo II. Though BM compounds promoted the formation of protein-DNA complexes in isolated nuclei and cells, this effect was undiminished when levels of topo II varied. The BM compounds had little activity in a topo II-mediated DNA cleavage assay, suggesting that they do not function as topo II poisons. Rather, BM-induced protein-DNA complex formation was likely due to the bifunctional alkylating reactivity of these compounds. Finally, the growth inhibitory properties of these compounds did not correlate with their ability to inhibit topo II, indicating that these compounds did not exert their cellular activity through inhibition of topo II. Some BM compounds reacted very quickly with glutathione and cysteine, likely initially through an electrophilic Michael addition. In the absence of cysteine, the growth inhibitory effects of BM were increased tenfold, indicating the modulatory effect of cysteine sulfhydryl adducts. EPR studies showed that a semiquinone-free radical was produced by some BM compounds. BM compounds likely exert their action through DNA cross-linking and/or by inducing oxidative stress. Although topo II is not a direct target of these agents, this enzyme may play a role in processing the consequences of direct DNA adduction and/or oxidative DNA damage.

3D Pharmacophore Model for Insect Repellent Activity and Discovery of New Repellent Candidates

To better understand the mechanism of insect repellency and to identify new repellent candidates, we performed a three-dimensional quantitative structure-activity (QSAR) study and developed a pharmacophore model for potent repellent activity from a set of eleven known diverse insect repellent compounds by using the CATALYST 3D-QSAR methodology. The protection time for repellent activity of the compounds was taken from an earlier published study. The pharmacophore was found to have three hydrophobic sites (two aliphatic and one aromatic) and a hydrogen-bond acceptor site in specific locations in the three dimensional geometry of the molecules that are critical for potent repellent activity. The pharmacophore showed an excellent correlation (correlation = 0.9) between the experimental protection time afforded by the compounds in the training set and their predicted protection time. The validity of the pharmacophore model goes beyond the list in the training set and is found to map well on a variety of other insect repellents. By mapping this model on one of the more potent analogue we have generated a three-dimensional shape based template which allowed a search of our in-house compound database and discover four new potential insect repellent candidates.

Tricyclic alkylamides as melatonin receptor ligands with antagonist or inverse agonist activity.

This work reports the design and synthesis of novel alkylamides, characterized by a dibenzo[a,d]cycloheptene nucleus, as melatonin (MLT) receptor ligands. The tricyclic scaffold was chosen on the basis of previous quantitative structure-activity studies on MT1 and MT2 antagonists, relating selective MT2 antagonism to the presence of an aromatic substituent out of the plane of the MLT indole ring. Some dibenzo seven-membered structures were thus selected because of the noncoplanar arrangement of their benzene rings, and an alkylamide chain was introduced to fit the requirements for MLT receptor binding, namely, dibenzocycloheptenes with an acylaminoalkyl side chain at position 10 and dibenzoazepines with this side chain originating from the nitrogen atom bridging the two phenyl rings. Binding affinity at human cloned MT1 and MT2 receptors was measured by 2-[125I]iodomelatonin displacement assay and intrinsic activity by the GTPgammaS test. The majority of the compounds were characterized by higher affinity at the MT2 than at the MT1 receptor and by very low intrinsic activity values, thus confirming the importance of the noncoplanar arrangement of the two aromatic rings for selective MT2 antagonism. Dibenzocycloheptenes generally displayed higher MT1 and MT 2affinity than dibenzoazepines. N-(8-Methoxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-ylmethyl)propionamide (4c) and -butyramide (4d) were the most selective MT2 receptor antagonists of the series, with MT2 receptor affinity comparable to that of melatonin and as such among the highest reported in the literature for MLT receptor antagonists. The acetamide derivative 4b produced a noticeable reduction of GTPgammaS binding at MT2 receptor, thus being among the few inverse agonists described.

Pharmacophore identification and 3D-QSAR studies in N-(2-benzoyl phenyl)-l-tyrosines as PPARγ agonists

The identification of pharmacophore and three dimensional quantitative structure–activity studies have been performed on a set of N-(2-Benzoylphenyl)-l-tyrosine for their PPARγ agonist activity by using the logico-structural based software Apex 3D—which describes the properties and distribution of primary and secondary biophore sites in the three dimensional space. Among several models, two models of comparable probability were selected on the basis of R2>0.60, chance ≤0.04, size <4, match >0.20. These models showed a good correlation between the observed and predicted biological activity both for training and test sets.

Quantitative structure–Activity relationship study on sulfanilamide schiff's bases: carbonic anhydrase (CA) inhibitors

The paper deals with quantitative structure–activity studies on a group of sulfanilamide Schiff's base inhibitors of carbonic anhydrase (CA) using distance-based topological indices. The regression analysis of the data has shown that the activities of the compounds used in inhibiting Carbonic AnhydraseII (CAII) activity can be modeled excellently in multi-parametric model in that some indicator parameters are also involved. The results are discussed critically.

Quantitative structure-activity studies of imidazolidinone benzene sulfonamides : human β3-adrenergic receptor agonists acting as antiobesity drugs

Substituted imidazolidinone benzene sulfonamides were reported to have high affinity for β 3 -adrenergic receptors of adiposites tissue. In order to establish an exact relationship between β 3 -adrenergic receptor agonisticactivity and various quantifying parameters, these compounds were subjected to quantitative structure-activity relationship (QSAR) analysis.

Quantitative structure-activity studies of insect growth regulators: XIX. Effects of substituents on the aromatic moiety of dibenzoylhydrazines on larvicidal activity against the beet armyworm Spodoptera exigua.

Larvicidal activity against the beet armyworm, Spodoptera exigua (Hübner), was measured after topical treatment for a series of N-tert-butyl-dibenzoylhydrazines having various substituents in the benzoyl (A-ring) moiety closer to the tert-butyl group, the other benzoyl (B-ring) moiety being unsubstituted. The effects of substituents on the larvicidal activity were analyzed using the classical quantitative structure-activity relationship (QSAR) procedure. Introduction of hydrophobic substituents with a small volume into any position was favourable to activity. The existence of electron-withdrawing substituents at ortho positions was also favourable to activity. For multi-substituted compounds, physico-chemically unknown unfavourable factors were suggested to remain after separating common substituent effects derived from QSAR for mono-substituted analogues. With the exception of the unsubstituted compound RH-5849, the effect of substituents in the A-ring moiety on the larvicidal activity was similar to those found with the lepidopteran rice stem borer, Chilo suppressalis (Walker). The larvicidal activity of RH-5849 against S exigua was significantly lower than the value predicted from the correlation between activities against S exigua and C suppressalis. Topical treatment with piperonyl butoxide, a synergist inhibiting oxidative metabolism, slightly enhanced the larvicidal activity of RH-5849 against S exigua.

Quantitative structure-activity studies of insect growth regulators: XVIII. Effects of substituents on the aromatic moiety of dibenzoylhydrazines on larvicidal activity against the Colorado potato beetle Leptinotarsa decemlineata.

Larvicidal activity against the Colorado potato beetle Leptinotarsa decemlineata (Say) was measured for a series of N-tert-butyl-dibenzoylhydrazines having various substituents on the benzoyl (A-ring) moiety nearer to the tert-butyl group, with the other benzoyl (B-ring) moiety being unsubstituted. The effects of these substituent on the larvicidal activity were analyzed using classical quantitative structure-activity relationship (QSAR) procedures. The effects of substituents on the A-ring moiety on larvicidal activity were entirely different from those against the lepidopteran rice stem borer Chilo suppressalis (Walker) previously reported. Position-specific steric and hydrophobic effects, as well as certain substitution patterns, were likely to participate in modifying the larvicidal activity. The activity of para-substituted compounds was generally lower than that of un-, ortho- and meta-substituted compounds. Most multi-substituted compounds showed an activity equivalent to or lower than that of the unsubstituted compound. Among 46 compounds tested, the 2-sec-butoxy analogue was most potent against L decemlineata, although this compound had previously been shown to be only weakly active against C suppressalis.

Comparative quantitative structure–activity study of radical scavengers

Classic and three-dimensional (3-D) QSAR analyses of 13 radical scavengers (1–13) were performed to derive two classic, two Apex–3-D and one comparative field analysis (CoMFA) models. Two classical models with predictive cross-validated r2 (Q2) over 0.96 indicated that the activity was attributed to the electronic COH and ELUMO, steric molar refractivity (MR) and lipophilic log P. Three-dimensional quantitative structure–activity relationship (3-D–QSAR) studies were performed by 3-D pharmacophore generation (Apex–3-D) and CoMFA techniques. For Apex–3-D studies, two best models with high Q2 (0.94 and 0.97) were yielded. Structural properties contributing to the activity were not only lipophilic but also the optimum steric property and geometry of side-chain composition. For CoMFA studies, the sp3C(+1) probe provided the best Q2 of 0.79 with steric and electrostatic contributions of 42.3 and 57.7%, respectively. The activity of four new compounds (14–17) not included in the derivation were predicted with these models. Although the derived models were from limited data, the statistic relation was predictive. The linear correlations between the experimental IC50 values and the predicted values from classical and Apex–3-D models were found to be high and significant. The predicted activity of 17 from CoMFA was much lower than the experimental value; this deviation occurred according to the missing of hydrophobic field in standard CoMFA study. In vitro and ex vivo antilipid peroxidation in mouse brain and ESR studies of 14–17 were investigated for the radical-scavenging ability. The difference between the in vitro results, antilipid peroxidation and electron spin resonance (ESR) and ex vivo results in coumarin series was found. Thus, other properties for good bioavailability besides log P should also be taken into consideration.

Glycosphingolipid depletion in Fabry disease lymphoblasts with potent inhibitors of glucosylceramide synthase

Fabry disease is an inherited X-linked disorder resulting in the loss of activity of the lysosomal hydrolase alpha-galactosidase A and causing the clinical manifestations of renal failure, cerebral vascular disease, and myocardial infarction. The phenotypic expression of this disorder is manifest by the accumulation of glycosphingolipids containing alpha-galactosyl linkages, most prominently globotriaosylceramide. Based on quantitative structure activity studies, we recently reported two newly designed glucosylceramide synthase inhibitors based on 1-phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol (P4). These inhibitors, 4'-hydroxy-P4 and ethylenedioxy-P4, were evaluated for their ability to deplete globotriaosylceramide and other glucosylceramide-based lipids in Fabry lymphocytes and were compared with N-butyldeoxynojirimycin, another reported glucosylceramide synthase inhibitor. Concentrations as low as 10 nmol/L of 4'-hydroxy-P4 and ethylenedioxy-P4 resulted in 70 and 80% depletion, respectively, of globotriaosylceramide, with maximal depletion occurring at three days of treatment. There was no impairment of cell growth. In contrast, N-butyldeoxynojirimycin only minimally lowered globotriaosylceramide levels, even at concentrations as high as 10 micromol/L. Globotriaosylceramide depletion was confirmed by the loss of binding of FITC-conjugated verotoxin B subunit to the lymphoblasts. These findings suggest that selective glucosylceramide synthase inhibitors are highly effective in the depletion of globotriaosylceramide from Fabry cell lines. We suggest that these compounds have potential therapeutic utility in the treatment of Fabry disease.

Prediction of IC50 values for ACAT inhibitors from molecular structure.

A quantitative structure-activity study is performed on several series of compounds derived from N-chlorosulfonyl isocyanate to develop models that relate their structures to IC50 activity for inhibition of acyl-CoA:cholesterol O-acyltransferase (ACAT). Numerical descriptors are used to encode topological, electronic, and geometric information from the molecular structures of the inhibitors. A data set of 157 compounds showing triglyceride- and cholesterol-lowering activity is used to develop successful linear regression models and nonlinear computational neural network models. The models are validated using an external prediction set.

Chroman amide and nicotinyl amide derivatives: Inhibition of lipid peroxidation and protection against head trauma

A series of chroman amide and nicotinyl amide derivatives was designed and synthesized for the treatment of traumatic and ischemic CNS injury. Five compounds were significantly more potent inhibitors of lipid peroxidation in vitro than the reference antioxidant, trolox (p < 0.01). Quantitative structure activity studies demonstrated that the inhibitory action was related to the ability to donate electrons, charge on hydroxy group and ELUMO, to scavenging radicals and to the lipophilicity log P, which determines penetration of membrane lipids. ESR study indicated the ability of 12 to scavenge the hydroxyl radicals. The most promising compound, [(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2yl)carbonyl]-3′-(aminoethyl) indole (12), inhibited ex vivo lipid peroxidation in a head injury model and showed potent in vivo neuroprotective efficacy. Improvement of neurological recovery within 1 h of injury (grip test score) by as much as 200% was observed together with significant anti-anoxia activity. Compound 12 was a potent antagonist of methamphetamine-induced hypermotility resulting from dopamine release in the mouse brain. These results support the importance of cerebroprotective radical-scavenging agents for the treatment of traumatic injury and anoxia as well as provide additional evidence for the role of oxygen radicals and dopamine in brain damage.

Quasi-orthogonal basis sets of molecular graph descriptors as a chemical diversity measure

In the pharmaceutical industry, the virtual screening of combinatorial libraries is used to rationally select compounds for biological testing from databases of hundreds of thousands of compounds. In addition to structural descriptors, such as fingerprints and pharmacophores, the application of relatively simple structural descriptors traditionally used in quantitative structure-activity studies offers speed and efficiency for rapidly measuring the molecular diversity of such collections. We explore new topological indices computed from the molecular graph as potential structural descriptors for the characterization of molecular diversity. A database of 2000 compounds randomly selected from the National Cancer Institute AIDS database was used to measure the intercorrelation of the descriptors. The initial collection of 240 structural descriptors was reduced to several quasi-orthogonal sets of up to 9 descriptors, using different thresholds for the maximum intercorrelation coefficient.

Three-dimensional quantitative structure–activity studies of octopaminergic agonists responsible for the inhibition of sex-pheromone production in Hercoverpa armigera

The quantitative structure–activity relationship (QSAR) of octopaminergic agonists responsible for the inhibition of sex-pheromone production in Hercoverpa armigera, was analyzed using physicochemical parameters, molecular shape analysis (MSA), molecular field analysis (MFA), and receptor surface model (RSM), respectively. The dose-response studies were performed in vitro analyzing the effect of these compounds on intracellular cAMP production in the presence of pheromone biosynthesis activating neuropeptide (PBAN) at 1 pmol/intersegment. Six active derivatives were identified in the order of decreasing pheromonostatic activity: 2-(2,6-dimethylanilino)imidazolide (6 ) >2-(2-methyl-4-chloroanilino)oxazolidine (1) >clonidine (5) >2-(2,6-diethylanilino)thiazolidine (8) >2-(3,5-dichlorobenzylamino)-2-oxazoline (4) >tolazoline (10) which were all active in the nanomolar range in inhibition of cAMP production by 1 pmol PBAN/intersegment. Four other compounds were less active having Ki in the micromolar range. An MSA was tried to obtain QSAR equation that incorporates spatial molecular similarity data of those compounds. MFA on the training set of those compounds evaluated effectively the energy between a probe and a molecular model at a series of points defined by a rectangular or spherical grid. An RSM was generated using some subset of the most active structures. Three-dimensional energetics descriptors were calculated from RSM/ligand interaction and these three-dimensional descriptors were used in QSAR analysis. These results indicate that these derivatives could provide useful information in the characterization and differentiation of octopaminergic receptor types and subtypes.

Quantitative structure–activity studies of insect growth regulators: XVI. Substituent effects of dibenzoylhydrazines on the insecticidal activity to Colorado potato beetle Leptinotarsa decemlineata

Quantitative structure–activity studies of insect growth regulators: XVI. Substituent effects of dibenzoylhydrazines on the insecticidal activity to Colorado potato beetle Leptinotarsa decemlineata

Quantitative structure-activity studies of insect growth regulators: XVI. Substituent effects of dibenzoylhydrazines on the insecticidal activity to Colorado potato beetleLeptinotarsa decemlineata

Insecticidal activity against the Colorado potato beetle, Leptinotarsa decemlineata, was measured for a series of substituted N-tert-butyl-dibenzoylhydrazines, in which one of the benzoyl moieties closer to the tert-butyl group was fixed as being 2-chloro-substitued and the other variously substituted singly or doubly. The effects of substituents on the activity were quantitatively analysed using the classical quantitative structure–activity relationship (QSAR) procedure. The activity against the Colorado potato beetle increases with the molecular hydrophobicity. In addition, various types of steric effect are at work, depending upon the positions. Hydrogen-bonding acceptor substituents at the para position enhance the activity. There seem to be threshold (or optimum) values, albeit position-dependent, in the molecular hydrophobicity, above which the activity starts to decrease. This biphasic contribution of the molecular hydrophobicity to activity against coleopterous larvae is the most conspicuous difference in substituent effects from those found for similar compounds against lepidopterous pest insects, and may be the basis of the variations in the activity spectrum for certain compounds in this series. The introduction of bulkier substituents into the meta- and para-positions of the benzene ring, apart from the tert-butyl group, is unfavorable to activity. LD50 values against Colorado potato beetle larvae of methoxyfenozide (RH-2485) and tebufenozide (RH-5992) were in the order of 10−7 mol per insect, whereas those of RH-5849, and halofenozide (RH-0345) were very low, 10−9–10−10 mol per insect being selective to the coleopterous larvae. © 1999 Society of Chemical Industry

Quantitative structure-activity studies of insect growth regulators: XVI. Substituent effects of dibenzoylhydrazines on the insecticidal activity to Colorado potato beetleLeptinotarsa decemlineata

Insecticidal activity against the Colorado potato beetle, Leptinotarsa decemlineata, was measured for a series of substituted N-tert-butyl-dibenzoylhydrazines, in which one of the benzoyl moieties closer to the tert-butyl group was fixed as being 2-chloro-substitued and the other variously substituted singly or doubly. The effects of substituents on the activity were quantitatively analysed using the classical quantitative structure–activity relationship (QSAR) procedure. The activity against the Colorado potato beetle increases with the molecular hydrophobicity. In addition, various types of steric effect are at work, depending upon the positions. Hydrogen-bonding acceptor substituents at the para position enhance the activity. There seem to be threshold (or optimum) values, albeit position-dependent, in the molecular hydrophobicity, above which the activity starts to decrease. This biphasic contribution of the molecular hydrophobicity to activity against coleopterous larvae is the most conspicuous difference in substituent effects from those found for similar compounds against lepidopterous pest insects, and may be the basis of the variations in the activity spectrum for certain compounds in this series. The introduction of bulkier substituents into the meta- and para-positions of the benzene ring, apart from the tert-butyl group, is unfavorable to activity. LD50 values against Colorado potato beetle larvae of methoxyfenozide (RH-2485) and tebufenozide (RH-5992) were in the order of 10−7 mol per insect, whereas those of RH-5849, and halofenozide (RH-0345) were very low, 10−9–10−10 mol per insect being selective to the coleopterous larvae. © 1999 Society of Chemical Industry

Quantitative structure–activity studies of octopaminergic ligands against Locusta migratoria and Periplaneta americana

Quantitative structure–activity studies of octopaminergic ligands against Locusta migratoria and Periplaneta americana

Quantitative structure–activity studies of insect growth regulators xiv. Three‐dimensional quantitative structure–activity relationship of ecdysone agonists including dibenzoylhydrazine analogs

Quantitative structure–activity studies of insect growth regulators xiv. Three‐dimensional quantitative structure–activity relationship of ecdysone agonists including dibenzoylhydrazine analogs

Quantitative structure-activity studies of insect growth regulators xiv. Three-dimensional quantitative structure-activity relationship of ecdysone agonists including dibenzoylhydrazine analogs

N-tert-Butyl-N,N'-dibenzoylhydrazines such as tebufenozide (RH-5992) mimic the action of a molting hormone, 20-hydroxyecdysone, and cause premature molting of larvae leading to their death. Previously, it was shown that one of the benzoyl moieties in dibenzoylhydrazines plays a role similar to that of the aliphatic side chain at the C-17 position of ecdysones. In the present study, N-benzoyl-N'-benzylhydrazine, N,N'-dibenzylhydrazine, and N-alkanoyl-N'-benzoylhydrazine analogs have been synthesized to compare the effects of two carbonyl groups as well as two benzene rings of dibenzoylhydrazine. The quantitative structure-activity relationship of ecdysone agonists including dibenzoylhydrazine analogs was analyzed three-dimensionally using the CoMFA (comparative molecular field analysis) procedure. The CoMFA results suggested that the two carbonyl oxygen atoms of the diacylhydrazine skeleton probably correspond to the oxygens of the 20- and 22-OH groups of ecdysones, and that the benzoyl moiety located closer to the tert-butyl group is important for retaining high activity.