Structure-activity relationship of new 2-substituted penem antibiotics

The antibacterial activities of three new penems with 4-hydroxyprolinamide, 1-prolinamide and N-methyl-N-2-propionamide substituents, respectively, in position 2 and of their stereoisomers were examined against Staphylococcus aureus, Enterococcus faecalis, Enterococcus faecium, Escherichia coli and Pseudomonas aeruginosa. All substitutes conferred a broad antibacterial spectrum on the penem moiety. Changes in stereoisomerism selectively improved the activity against E. coli, S. aureus or enterococci. The structure-activity relationships of each compound were discussed in relation to minimum inhibitory concentrations, penicillin-binding protein (PBP) affinity and outer membrane permeability coefficient in E. coli. In this microorganism, PBP 2 was the target for all compounds. Changes in stereoisomerism influenced the affinity for PBPs 1A/B and 2. All antibiotics easily permeated the outer membrane of E. coli and, within each group of compounds, the penetration rate correlated with the antibacterial activity.     

Structure-activity relationships of protoberberines having antimicrobial activity

13-Alkyl derivatives (2-6 and 8-12) of berberine (1) and palmatine (7) were subjected to in vitro antibacterial activity tests against Bacillus subtilis and Salmonella enteritidis. Antibacterial activity increased as the length of the C-13 aliphatic side chain increased. The effects of the oxygen-substituents on aromatic rings A, C, and D of protoberberinium salts 13-20 on the antimicrobial activity against Staphylococcus aureus, B. subtilis, S. enteritidis, Escherichia coli, and Candida albicans are also discussed. The change in lipophilicity of the protoberberinium salts caused by modification of the substituents appears to influence the antibacterial activity. 13-Hexylberberine (6) and 13-hexylpalmatine (12) exhibited the greatest antibacterial activity.     

Semisynthetic beta-lactam antibiotics. 8 Structure-activity relationships of alpha-sulfocephalosporins

Synthesis and in vitro activity of a number of cephalosporins having alpha-sulfoacyl- or other acyl groups, e.g., alpha-carboxyacyl- and alpha-sulfoaminoacyl- at the 7-position and bearing a variety of heterocyclic thioether or pyridinium moieties at the 3-position are described.     

Dimensions of affect relationships: Models and their integrative implications.

This article presents data from a number of areas of psychology that have dealt with the issue of whether positive and negative affects are independent--the bivariate view--or whether they operate inversely from each other--the unidimensional, bipolar view. Both models have extensive empirical support. A more integrative view, the Dynamic Model of Affect (DMA), specifies conditions under which both bivariate and bipolar models are valid. It is tailored to analyzing both affect systems functioning concurrently. The DMA is reviewed and then extended to show how 3 major areas of research can begin to incorporate the more integrative framework of analyzing co-occurring types of affect. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Structure-activity relationships of indole- and pyrrole-derived cannabinoids

Early molecular modeling studies with Delta9-tetrahydrocannabinol (Delta9-THC) reported that three discrete regions which interact with brain cannabinoid (CB1) receptors corresponded to the C-9 position of the cyclohexene ring, the phenolic hydroxyl and the carbon side chain at the C3 position. Although the location of these attachment points for aminoalkylindoles is less clear, the naphthalene ring, the carbonyl group and the morpholinoethyl group have been suggested as probable sites. In this study, a series of indole- and pyrrole-derived cannabinoids was developed, in which the morpholinoethyl group was replaced with another cyclic structure or with a carbon chain that more directly corresponded to the side chain of Delta9-THC and were tested for CB1 binding affinity and in a battery of in vivo tests, including hypomobility, antinociception, hypothermia and catalepsy in mice and discriminative stimulus effects in rats. Receptor affinity and potency of these novel cannabinoids were related to the length of the carbon chain. Short side chains resulted in inactive compounds, whereas chains with 4 to 6 carbons produced optimal in vitro and in vivo activity. Pyrrole-derived cannabinoids were consistently less potent than were the corresponding indole derivatives and showed pronounced separation of activity, in that potencies for hypomobility and antinociception were severalfold higher than potencies for hypothermia and ring immobility. These results suggest that, whereas the site of the morpholinoethyl group in these cannabinoids seems crucial for attachment to CB1 receptors, the exact structural constraints on this part of the molecule are not as strict as previously thought.     

Structure-activity relationships of sandalwood odorants: synthesis and odour of methyl-beta-santalol

The synthesis and odour properties of the new santalol analogue, methyl-beta-santalol, are described. The additional methyl group adjacent to the hydroxyl function of the standard molecule, beta-santalol, deprives the new compound of the sandalwood note. The synthesis and the odour evaluation of this compound supports the proposed model for sandalwood fragrance as it shows that the methyl group located at the osmophoric center prevents association of the molecule with the hypothetical receptor.     

Structure-activity relationships of cysteine esters and their effects on thiol levels in rat lung in vitro

Pretreatment with cysteine esters increases cysteine (CySH) levels in rat lung and protects against the lethal effects of inhaled perfluoroisobutene in vivo. There are marked differences in the duration of protection achieved with different cysteine esters. In this study we have compared the uptake and metabolism of CySH, N-acetyl cysteine (NAc), cysteine esters and cystine esters in vitro using rat lung and liver homogenates and lung slices. Liver homogenates metabolized CySH and cysteine esters faster than lung homogenates. The half life (T1/2) of CySH in lung was 58.8 +/- 17.3 min and in liver was 14.0 +/- 1.6 min (mean +/- SEM). T1/2 of the esters in lung ranged between 6.5 and 12.1 min and in liver between 1.9 and 5.3 min. Cysteine tertiary butyl ester, which does not protect in vivo, was not hydrolysed to CySH by lung or liver homogenates. All esters increased and prolonged intracellular CySH concentrations in lung slices to a much greater extent than CySH itself. NAc did not raise intracellular CySH above that of the controls and no NAc appeared within the slice. After CySH incubation intracellular CySH was 0.9 +/- 0.1 nmol/mg wet wt at 10 min whereas after incubation with the esters it ranged between 2.60 and 3.65 nmol/mg wet wt. Cysteine cyclohexyl ester prolonged the increase of CySH the longest and cysteine methyl ester the shortest. CySH levels with cysteine cyclohexyl ester were 2.74 +/- 0.15 and 4.13 +/- 0.37 nmol/mg wet wt at 10 and 60 min, respectively, whereas with cysteine methyl ester, CySH levels were 2.60 +/- 0.5 and 1.25 +/- 0.08 nmol/mg wet wt at similar times. Cystine esters increased intracellular concentrations of both cystine and CySH. CySH concentrations ranged between 2.92 and 3.19 nmol/mg wet wt and cystine between 1.39 and 1.47 nmol/mg wet wt at 60 min. The elevation and duration of CySH in lung slices is well correlated with the duration of protection against perfluoroisobutene achieved in vivo.     

Prospects for the direct electron crystallographic determination of zeolite structures

Recently two successful zeolite structures based on experimental electron crystallographic data have been published. Diffraction and image data based on the silicate portion of the zeolite, mordenite, which are perturbed by dynamical (as well as secondary) scattering, have been simulated by a multiple-beam dynamical scattering program. Structure analyses with these data show that the above claims are not unreasonable, given a high enough accelerating voltage for the electron beam. If, for example, 2.9 A resolution micrographs are taken from a 120 A thick crystal in a 200 or 400 kV electron microscope, the crystallographic phases found by image analysis (Fourier filtration) are accurate enough to be extended by the Sayre equation to the (atomic) resolution limit of the electron diffraction pattern (for example from a 105 A thick crystal illuminated by a 1,200 kV electron source). The resultant potential map can be interpreted to find most of the atomic positions and the remaining ones will appear during the progress of a Fourier refinement.     

6-Alkylandrosta-4,6-diene-3,17-diones and their 1,4,6-triene analogs as aromatase inhibitors. Structure-activity relationships

Two series of 6-alkylandrosta-4,6-diene-3,17-diones (5) and their 1,4,6-triene analogs 6 were synthesized as aromatase inhibitors to gain insight into the structure-activity relationship between varying the 6-n-alkyl substituents (C1-C7) and inhibitory activity. All of the steroids synthesized were extremely powerful competitive inhibitors of aromatase in human placental microsomes, with apparent Ki values for the 6-alkyl-4,6-diene steroids 5 ranging from 17 to 36 nM and with those for the 1,4,6-triene steroids 6 ranging from 2.5 to 58 nM. The 6-ethyl-1,4,6-triene compound 6b (Ki = 2.5 nM) was the most potent inhibitor among them. The 6-alkyl-1,4,6-triene steroids 6, except for the 6-methyl analog 6a, and higher affinity for aromatase than the natural substrate androstenedione (K(m) = 24 nM), and their inhibitory activities were more potent than the corresponding 4,6-diene steroids 5. In a series of the 4,6-diene steroids 5, compounds 5c-f with the n-alkyl chain substituents (C3 to C6) also had slightly higher affinity than androstenedione for dromatase. All of the 1,4,6-triene steroids 6 inactivated aromatase in a time-dependent manner, with k(inact) values ranging from 0.021 to 0.074 min-1; in contrast, the 4,6-diene analogs 5 did not. The inactivation was prevented by androstenedione, and no significant effect of L-cysteine on the inactivation was observed in each case. These results indicate that the length of the n-alkyl substituent at C-6 of androsta-1,4,6-triene-3,17-dione (6h), rather than its 4,6-diene analog 5h, plays a critical role in tight binding to the active site of aromatase. No significant correlation was observed between affinity for the enzyme and the inactivation ability of the 6-alkyl-1,4,6-trienes.     

Structure-activity relationships and physico-chemical properties of synthetic lipopeptide inhibitors of PKC

Four synthetic lipopeptides, (K-pm 19,31), (K-pm 19,21,31), (K-pm 19,28,31) and (K-pm 19,21,28,31) with the lysine-palmitoyl (K-pm) residue as a lipophilic moiety, based on the pseudosubstrate sequence 19RFARKGALRQKNV31 (R19-V31), were found to be potent protein kinase C (PKC) inhibitors. However, the lipopeptides (K-pm 19,21,31), (K-pm 19,28,31) and (K-pm 19,21,28,31) were also found to act as protein kinase cAMP-dependent (PKA) inhibitors. Peptide (K-pm 19,31), the least water soluble, is marginally selective towards PKC, unlike the other palmitoyl derivatives studied here. Since the non-palmitoylated analogues (K 19,31), (K-ac 19,31), (K 19,21,31) and (K-ac 19,21,31) were inhibitors of PKC but not of PKA, the palmitoyl moiety must play a role in the specificity of protein kinase inhibition. In vitro, the lipophilic peptides showed greater stability to protease-mediated hydrolysis than the pseudosubstrate peptide depending upon the number of lipophilic (K-pm) residues. CD studies showed that in comparison with the peptide analogues, the remarkable resistance of the pseudosubstrate (R19-V31) to adopt an alpha-helix conformation in TFE, known to be strongly alpha-helix inducing, rules out this structure as the peptide binding conformation to PKC. By contrast, in aqueous media all the peptides show an extended conformation that correlates well with their inhibitory activity. This is in compliance with the crystallographic observation that an extended structure has been observed for the (5-24) PKI peptide inhibitor bound to PKA.     

Structure-activity relationships of benzimidazoles and related heterocycles as topoisomerase I poisons

A series of substituted 2-(4-methoxyphenyl)-1H-benzimidazoles were synthesized and evaluated as inhibitors of topoisomerase I. The presence of a 5-formyl-, 5-(aminocarbonyl)-, or 5-nitro group (i.e., substituents capable of acting as hydrogen bond acceptors) correlated with the potential of select derivatives to inhibit topoisomerase I. In contrast to bi- and terbenzimidazoles, the substituted benzimidazoles that were active as topoisomerase I poisons exhibited minimum or no DNA binding affinity. 5-Nitro-2-(4-methoxyphenyl)-1H-benzimidazole exhibited the highest activity and was significantly more active than the 4-nitro positional isomer. The 5- and 6-nitro derivatives of 2-(4-methoxyphenyl) benzoxazole, 2-(4-methoxyphenyl)benzothiazole, and 2-(4-methoxyphenyl)indole were synthesized and their relative activity as topoisomerase I inhibitors determined. None of these heterocyclic analogues were effective in significantly inhibiting cleavable-complex formation in the presence of DNA and topoisomerase I, suggesting a high degree of structural specificity associated with the interaction of these substituted benzimidazoles with the enzyme or the enzyme-DNA complex. In evaluating their cytotoxicity, these new topoisomerase I poisons also exhibited no significant cross-resistance against cell lines that express camptothecin-resistant topoisomerase I.     

Attention-deficit hyperactivity disorder and substance abuse: relationships and implications for treatment

Attention-deficit hyperactivity disorder (ADHD) and substance-use disorders are related to each other in a variety of ways. Although within the child-psychiatry literature earlier investigations were inconsistent regarding such a link, recent prospective studies that followed hyperactive children and normal controls into adulthood have found that hyperactive adults with a history of ADHD are more likely than controls to have substance-use disorders. The substance-abuse literature is less consistent regarding the potential association between ADHD and substance abuse. However, recent studies suggest that persons with a substance-use disorder, and particularly those with a cocaine-use disorder, may be more likely than the general population to have a childhood history of ADHD. Some of the inconsistency regarding this association is due to differences in diagnostic criteria, type of assessments used, and reliability of information obtained. Each of the potential relationships that may exist between ADHD and substance abuse has treatment implications for the clinician. Pharmacological as well as nonpharmacological approaches deserve further investigation. Because pharmacotherapy is a central component in the treatment of childhood ADHD, clinicians designing a strategy to treat both a substance-use disorder and ADHD need to consider pharmacological interventions. At present, the literature on pharmacological treatment for childhood ADHD is extensive and that for adult ADHD is growing; information regarding the treatment of cocaine abuse and concomitant ADHD symptoms remains limited.     

Nonlinear genetic relationships between traits and their implications on the estimation of genetic parameters

To estimate nonlinear genetic relationships between traits, formulas based on the paternal halfsib analysis theory were derived. To illustrate the usefulness of the formulas, a series of data sets with halfsib structure for some preselected parameters and sample size situations were generated by means of Monte Carlo techniques. When a nonlinear relationship in the form of a polynomial relationship of degree two is present, the linear and quadratic regression coefficients can be estimated from a paternal halfsib analysis without bias. Some of the traditional linear genetic parameters need correction; however, their value is limited if the relationship between two traits is nonlinear. Although regression coefficients may be estimated appropriately in many situations, the application of the described method is restricted to situations in which the causal flow between the traits involved is clear and the heritability of the determining trait is larger than approximately .10. Further work should be directed to investigation of possibilities for including such parameters in selection decisions in a formalized way.     

The implications of head injury for family relationships

Many of those sustaining head injury recover to the point that they no longer require hospital care. However, the family frequently has to cope with an individual with varying degrees of disability involving physical, psychological, cognitive and social dysfunctioning. This review of the literature briefly considers the possible effects that head injury may have for the injured person before going on to discuss the consequences that such an injury may have for the family of that individual. The family's need for information and education is highlighted and it is suggested that the nurse has an important role to play in this context.