Quantitative structure-activity relationships involving the inhibition of glycolic acid oxidase by derivatives of glycolic and glyoxylic acids.

The enzyme glycolic acid oxidase oxidizes glycolate to glyoxylate and glyoxylate to oxalate. Three series of compounds related to the natural substrates, substituted glycolic, oxyacetic, and glyoxylic acids, have been investigated as inhibitors of this enzyme using the techniques of regression analysis and quantitative structure-activity relationships. The best overall correlation with inhibitory potencies was found with the Hansch hydrophobic parameter pi. The classical electronic parameters sigmap, sigmam, F, and R performed poorly. For the substituted glyoxylic acids, a dummy parameter relating to the presence of a nucleophilic group in close proximity to the alpha-carbonyl of the glyoxylate group was found to be highly significant. The syntheses of six novel glycolic and glyoxylic acids are described.     

Quantitative structure-activity relationships of benzamide derivatives for anti-leukotriene activities.

To determine the structural requirements of the benzamide derivatives reported by Nakai et al. (J. Med. Chem. 1988, 31, 84-91) for antileukotriene activity, we studied their conformational characteristics in comparison with those of leukotriene. By superimpositions of the conformations of antagonists on that of leukotriene, we found that the conformations of the conjugated benzamide moiety, tetrazole ring, and benzopyran or benzodioxan ring of the antagonists correspond to the triene moiety, peptide carboxylic acid residue, and cysteine residue of leukotriene, respectively, but that no moiety of the antagonists corresponds to the terminal aliphatic carboxylic acid moiety of leukotriene. Furthermore, the stable conformations of alkyl and alkoxy groups of the antagonists were quite different from that of the omega-chain of leukotriene. However, conformational analyses taking all the possible rotations of these flexible chains into consideration showed that antagonists in which these flexible chains can most feasibly adopt the same lengths as those of the omega-chain exhibit potent antagonist activity. From these results, we deduced the structural features of benzamide derivatives necessary for potent antileukotriene activity.     

Quantitative structure-activity relationships study of a series of imidazole derivatives as potential new antifungal drugs

The Quantitative Structure-Activity Relationships (QSAR) has been developed to relate antifungal activity against Candida albicans and Rhodotorula glutinis of new imidazole derivatives with their physico-chemical and structural properties. For 265 imidazole derivatives the most significant statistically equations has been obtained with correlation coefficients R=0.800 and R=0.820 in case of activity against Ca. and Rh.g., respectively. The overall antifungal activity has been described by means of size and bulkiness related parameters as well as polar and lipophilic interactions. The significance of lipophilicity in terms of n-octanol/water partition coefficient, ClogP, on antifungal potency against both fungi has been investigated. QSAR equations for different classes of antifungal activity have been obtained. With a very high probability level (92% and 96%) the weak or very weak antifungal potency against C.a. can be determined and thus the number of required experiments can be reduced.     

Synthesis and structure-activity relationships of 5-substituted 6,8-difluoroquinolones, including sparfloxacin, a new quinolone antibacterial agent with improved potency

A series of 5,7-disubstituted 1-cyclopropyl-6,8-difluoro-4(1H)-oxoquinoline-3-carboxylic acids (10-36) were prepared; the C-5 substituent in these compounds comprised halo, hydroxy, mercapto, and amino groups and the C-7 functional group included variously substituted piperazines. In vitro antibacterial screening results indicated that the amino group was optimal among the C-5 substituents. A combination of the C-5 amino group and the C-7 3,5-dimethylpiperazinyl appendage in this series conferred the best overall antibacterial property with lack of adverse drug interactions. Compound 36k [named sparfloxacin, originally AT-4140, 5-amino-1-cyclopropyl-6,8-difluoro-7-(cis-3,5-dimethyl-1-piperazinyl)- 4(1H)-oxoquinoline-3-carboxylic acid] was superior to ciprofloxacin in both in vitro and in vivo potency and hence was selected as a promising candidate for an improved therapeutic agent.     

Design and synthesis of some new theophylline derivatives with bronchodilator and antibacterial activities

Methylxanthines especially theophylline have been recognized as potent bronchodilators for the relief of acute asthma for over 65 years. Recently, it was found that bacterial infection plays a role in asthma pathogenesis. Accordingly, the present work involves the synthesis of 6-(4-(un)substituted phenyl)thiazolo[2,3-f]theophyllines 2a–g and different series of 8-(1,2,4-triazol-3-ylmethylthio)theophyllines 6–9. The chemical structures of the target compounds were proved by IR, ¹H NMR, ¹³C NMR, EI-MS and HRMS spectroscopic techniques along with elemental analyses. The bronchodilator activity of fifteen compounds was determined in vivo by acetylcholine induced bronchospasm in anaesthetized guinea pigs. Results revealed that all compounds showed moderate to good activity; in addition, five compounds exhibited a bronchodilator activity nearly similar to that of aminophylline as a standard. The antibacterial activity of all the target compounds was investigated in vitro against both Gram-positive and Gram-negative bacterial strains. Results revealed that some compounds showed more potent antibacterial activity than ampicillin as a standard. Acute toxicity study for four target compounds revealed that none of these derivatives showed significant toxicity up to 300 mg/kg. It was found that compound 8c combined both promising bronchodilator and antibacterial activities. This compound could be subjected for further investigations as a new possible candidate in the treatment of bronchial asthma.     

Decarboxylase inhibition and structure-activity relationship studies with some newly synthetized benzyloxyamine and pyridylmethoxyamine derivatives

Decarboxylase inhibiting properties and the structure-activity relationship have been studied with a number of newly synthetized benzyloxyamines and pyridylmethoxyamines. In the case of benzyloxyamines, the 3-hydroxyl group, and in that of pyridylmethoxyamines, the position of methoxyamine group in the molecule, appear to be of special importance for inhibition of aromatic l-amino acid decarboxylase. We did not find any close relationship between specific histidine decarboxylase inhibiting effect and chemical structure. 3-Hydroxy-4-nitrobenzyloxyamine and pyridyl-3-methoxyamine were the most active compounds in these series. The former compound affected markedly both aromatic l-amino acid decarboxylase and histidine decarboxylase in vitro and in vivo and produced a significant decrease in the levels of histamine in the stomach and in the lungs. The latter compound proved to be a specific inhibitor of histidine decarboxylase and had a more pronounced effect on the tissue histamine levels than most of new and old benzyloxyamine derivatives.     

Quantitative structure-activity relationships and molecular graphics in ligand receptor interactions: amidine inhibition of trypsin

Quantitative structure-activity relationships have been formulated for four sets of amidine inhibitors of trypsin. The quantitative results from these equations are compared with qualitative models constructed from the X-ray crystallographic coordinates of a benzamidine bound to trypsin. The good agreement between the mathematical and graphics models provides further support for the use of substituent constants and regression analysis in the study of enzyme-ligand interactions.     

Fenbufen, a new anti-inflammatory analgesic: synthesis and structure-activity relationships of analogs.

One hundred analogs of fenbufen were prepared and tested using the carrageenan, polyarthritis, and UV erythema anti-inflammatory tests and the 2-phenyl-1,4-benzoquinone writhing and inflamed paw pressure analgesic tests. Only three retained the same full spectrum of activity as fenbufen: dl-4-(4-biphenylyl)-4-hydroxybutyric acid, dl-4-(4-biphenylyl)-1,4-butanediol, and 4-biphenylacetic acid. Fenbufen had the same spectrum of activity as aspirin, phenylbutazone, and indomethacin in the five tests. In addition, dose-response derived potencies show fenbufen more potent than aspirin and at least as potent as phenylbutazone in all five tests. Two related compounds were generally similar.     

Gate-dependent blockade of sodium channels by phenothiazine derivatives: structure-activity relationships.

Voltage-clamp studies of myelinated nerve fibers that are designed to determine structural criteria regarding selective drug blocking of open and inactive states of the sodium channel are described. A series of phenothiazines were studied. It was shown that two of these drugs (ethmozine and ethacizine, at 5 microM) require open channels for blocking action and the other two (chlorpromazine and chloracizine, at 5 microM) can effectively block inactive channels. A size criterion, which looks at the spanning width at the aromatic end of these molecules, can explain this qualitative difference in drug action. Other important differences in the action of these four drugs are described, including their rates of development of drug block and removal of drug block. Relevant critiques of proposed structure-activity hypotheses are given.     

Inhibition of nucleic acids and protein synthesis by deazaadenosine derivatives: a study on structure-activity relationships

The effect of four deaza-analogues of adenosine on the synthesis of nucleic acids and proteins was investigated in monkey kidney cell line Vero. Cells in exponential growth phase were exposed for two hours to 1, 3 or 10 microM concentrations of 1-deazaadenosine (c1Ado), 3-deazaadenosine (c3Ado), 7-deazaadenosine (c7Ado) or 1,3-dideazaadenosine (c1,3Ado) in a serum free medium; the rate of macromolecules synthesis was estimated after one hour pulse treatment with radiolabelled precursors. At the concentrations used, c1Ado and c3Ado produced no or very little change in the rate of macromolecules synthesis: c1Ado slightly increased RNA synthesis whereas c3Ado was a weak inhibitor of DNA synthesis. Conversely, c7Ado was a potent inhibitor of macromolecules synthesis. Two hours of drug exposure at a concentration of 10 microM, resulted in a 40-50% inhibition in DNA, RNA and protein synthesis rates. c1,3Ado did not significantly affect RNA or protein metabolism but produced a dramatic increase in DNA synthesis. No DNA breaks could be detected in cells exposed to the agents tested in this study.     

Protein kinase C inhibition by plant flavonoids. Kinetic mechanisms and structure-activity relationships

Protein kinase C (PKC) from rat brain was inhibited by plant flavonoids in a concentration-dependent manner depending on flavonoid structure. Of the fifteen flavonoids studied, fisetin, quercetin and luteolin were the most potent, while hesperetin, taxifolin and rutin were among the least potent. The flavonol fisetin was almost 100% inhibitory at a concentration of 100 microM. The extent of inhibition was the same whether diacylglycerol or 12-O-tetradecanoylphorbol-13-acetate was used as enzyme activator. Inhibition was independent of Ca2+, phospholipid, and enzyme activator, as shown by inhibition of protamine phosphorylation in the absence of the regulatory components. Fisetin was a competitive inhibitor with respect to ATP binding and noncompetitive with respect to protein substrate. The X-ray crystal structure analysis of hesperetin monohydrate showed that the molecule is essentially planar despite the sofa conformation of the gamma-pyran ring and the 27 degrees twist of the 2-phenyl ring. Comparison of this inactive flavanone with those of the active flavones showed that, although hesperetin can adopt a planar profile similar to those of fisetin and quercetin, the 4'-methoxy substituent blocks an essential structural feature required for inhibitory activity. Analysis of these structure-activity data revealed a model of the minimal essential features required for PKC inhibition by flavonoids: a coplanar flavone structure with free hydroxyl substituents at the 3', 4' and 7-positions.     

Quantitative structure-activity relationships in 2,5-bis(1-aziridinyl)-p-benzoquinone derivatives against leukemia L-1210.

Antileukemic activities of more than 30 2,5-bis(1-aziridinyl)-p-benzoquinones (4) were correlated against well-defined physicochemical constants. These compounds were evaluated against lymphoid leukemia L1210 in BDF1 mice. The best equations obtained exhibited a linear dependence on the hydrophobic constant, pi. Characteristic aspects of the equations are that the larger the relative hydrophilicity of the drugs the stronger the antileukemic activity will be and that the more hydrophilic compounds have a greater chemotherapeutic index. Steric and electronic effects were also determined to be important. Based on the correlations, three compounds (11, 15 and 19) were designed, synthesized, and biologically evaluated.     

Immunomodulation by the new synthetic thiazole derivative tiprotimod. 1st communication: synthesis and structure-activity relationships

A series of carboxyalkylthio-substituted thiazole-carboxylic acids was synthesized and examined for macrophage activation and stimulation of the DTH (delayed type of hypersensitivity)-reaction. The structure-activity relationship in this series of new immunomodulators is discussed. Broadest immunological activity was seen for [2-(3-carboxy-1-propylthio)-4-methyl-1,3-thiazole]acetic acid (tiprotimod, HBW 538) which was selected for further studies.     

4,5-dihydro-1H-pyrazole derivatives with inhibitory nNOS activity in rat brain: synthesis and structure-activity relationships

In an attempt to find new compounds with neuroprotective activity, we have designed, synthesized and characterized 19 new nNOS inhibitors with a 4,5-dihydro-1H-pyrazole structure. Compounds 11r [1-cyclopropanecarbonyl-3-(2-amino-5-chlorophenyl)-4,5-dihydro-1H-pyrazole] and 11e [1-cyclopropanecarbonyl-3-(2-amino-5-methoxyphenyl)- 4,5-dihydro-1H-pyrazole] show the highest activities with inhibition percentages of 70% and 62%, respectively. A structure-activity relationship for the nNOS inhibition can be established from the structural comparison of these new pyrazole derivatives and the described synthetic kynurenines 10.     

Quantitative structure-activity relationships of the metabolism of drugs by uridine diphosphate glucuronosyltransferase.

Quantitative structure-activity relationships of the metabolism of drugs by uridine diphosphate (UDP)-glucuronosyltransferase have been investigated. It is observed that most of the variation in the rate of glucuronidation of phenols, thiols, and some other miscellaneous compounds can be accounted for by the lipophilic property of the molecules. The results are consistent with the previous finding with primary and secondary alcohols, and benzoic acids. The optimum lipophilicity for these compounds undergoing metabolism by UDP-glucuronosyltransferase appears to be a log P of 2.