Linked randomised controlled trials of face-to-face and electronic brief intervention methods to prevent alcohol related harm in young people aged 14–17 years presenting to Emergency Departments (SIPS junior)

Background: Alcohol is a major global threat to public health. Although the main burden of chronic alcohol-related disease is in adults, its foundations often lie in adolescence. Alcohol consumption and related harm increase steeply from the age of 12 until 20 years. Several trials focusing upon young people have reported significant positive effects of brief interventions on a range of alcohol consumption outcomes. A recent review of reviews also suggests that electronic brief interventions (eBIs) using internet and smartphone technologies may markedly reduce alcohol consumption compared with minimal or no intervention controls. Interventions that target non-drinking youth are known to delay the onset of drinking behaviours. Web based alcohol interventions for adolescents also demonstrate significantly greater reductions in consumption and harm among ‘high-risk’ drinkers; however changes in risk status at follow-up for non-drinkers or low-risk drinkers have not been assessed in controlled trials of brief alcohol interventions

Data from: Rapid assessment of conformational preferences in biaryl and aryl carbonyl fragments

The ability to rapidly assess the preferred conformation of key fragments in a structure "by visual inspection" is a very useful starting point in the process of drug design. With the ability to do so, one could address questions like: "How could we avoid planarity in a molecule?", "Will a molecule change its conformational preference if we make it more or less basic?" or "How does this electronic repulsion affect the conformational preference in the system?" in timely fashion. In this paper, we describe how the conformational energy profile (CEP, plot of energy as a function of dihedral bond angle) of a fragment can be interpreted through the understanding the interplay between resonance stabilization, steric effects and electrostatic interactions. Fifty-nine biaryl and aryl carbonyl fragments present in oral drugs or which are close derivatives thereof were selected. Calculation of their CEPs using ab initio methodology allowed us to conclude the relative importance of these factors in the conformational preference of these fragments as follows: steric repulsion > lone pair - lone pair repulsion > lone pair - fluorine repulsion > resonance stabilization and, to formulate "rules of thumb" that the practicing medicinal/organic chemist can apply when analysing molecules that contain these fragments

Data from: Rapid assessment of conformational preferences in biaryl and aryl carbonyl fragments

The ability to rapidly assess the preferred conformation of key fragments in a structure "by visual inspection" is a very useful starting point in the process of drug design. With the ability to do so, one could address questions like: "How could we avoid planarity in a molecule?", "Will a molecule change its conformational preference if we make it more or less basic?" or "How does this electronic repulsion affect the conformational preference in the system?" in timely fashion. In this paper, we describe how the conformational energy profile (CEP, plot of energy as a function of dihedral bond angle) of a fragment can be interpreted through the understanding the interplay between resonance stabilization, steric effects and electrostatic interactions. Fifty-nine biaryl and aryl carbonyl fragments present in oral drugs or which are close derivatives thereof were selected. Calculation of their CEPs using ab initio methodology allowed us to conclude the relative importance of these factors in the conformational preference of these fragments as follows: steric repulsion > lone pair - lone pair repulsion > lone pair - fluorine repulsion > resonance stabilization and, to formulate "rules of thumb" that the practicing medicinal/organic chemist can apply when analysing molecules that contain these fragments

Rapid assessment of conformational preferences in biaryl and aryl carbonyl fragments

<div><p>The ability to rapidly assess the preferred conformation of key fragments in a structure “by visual inspection” is a very useful starting point in the process of drug design. With the ability to do so, one could address questions like: “How could we avoid planarity in a molecule?”, “Will a molecule change its conformational preference if we make it more or less basic?” or “How does this electronic repulsion affect the conformational preference in the system?” in timely fashion. In this paper, we describe how the conformational energy profile (CEP, plot of energy as a function of dihedral bond angle) of a fragment can be interpreted through the understanding the interplay between resonance stabilization, steric effects and electrostatic interactions. Fifty-nine biaryl and aryl carbonyl fragments present in oral drugs or which are close derivatives thereof were selected. Calculation of their CEPs using <i>ab initio</i> methodology allowed us to conclude the relative importance of these factors in the conformational preference of these fragments as follows: “steric repulsion > lone pair—lone pair repulsion > lone pair—fluorine repulsion > resonance stabilization” and to formulate “rules of thumb” that the practicing medicinal/organic chemist can apply when analysing molecules that contain these fragments.</p></div

Comparison of the CEPs of 5, 8 and 9 with their corresponding charge-separated resonance forms.

<p>Comparison of the CEPs of 5, 8 and 9 with their corresponding charge-separated resonance forms.</p

CEPs of 2-alkylbiphenyls (ethyl, <i>iso</i>-propyl and <i>tert</i>-butyl, 20–22) and the comparison with biphenyl (1) and its methyl analogue (15).

<p>CEPs of 2-alkylbiphenyls (ethyl, <i>iso</i>-propyl and <i>tert</i>-butyl, 20–22) and the comparison with biphenyl (1) and its methyl analogue (15).</p

Rapid assessment of conformational preferences in biaryl and aryl carbonyl fragments - Fig 5

<p>a) CEPs of several <i>N</i>-phenylpyrrole derivatives, b) Charge-separated resonance stabilization of 4-cyano-phenyl-pyrrole (11), c) CEPs of several <i>N-</i>pyridinepyrrole derivatives, d) Charge-separated resonance stabilization of 4-cyano-phenyl-pyrrole (14).</p

Effect of methylated amides in the CEP profile of benzamides 48, 51 and 52.

<p>Effect of methylated amides in the CEP profile of benzamides 48, 51 and 52.</p

Aromatic biaryl systems distributed in three groups based on the major factor that leads to their corresponding CEP.

<p>The dihedral angle being studied in each of the fragments is indicated with stars, with the orientation as drawn defining 0°. Table indicates the figure where each CEP is represented in the paper.</p

Rapid assessment of conformational preferences in biaryl and aryl carbonyl fragments - Fig 8

<p>a) CEPs of a series of 2-halobiphenyls (23–26) and comparison with biphenyl 1 and 2-methylbiphenyl 15; b) Electrostatic fluorine—pi cloud aromatic ring attraction and repulsion.</p