Novel quorum sensing inhibitors targeting PqsR

Pseudomonas aeruginosa, a ubiquitous Gram-negative bacterium is counted among the most clinical relevant pathogens according to the World Health Organization (WHO). The opportunistic pathogen is able to form biofilms and persister cells, which makes it hard to eradicate and renders common antibiotic treatment ineffective. These factors are under control of the Pseudomonas Quinolone Signal (PQS) quorum sensing (QS) system, which thereofre displays an attractive drug target. This work describes the design and synthesis of novel PqsR inverse agonists based on a previously described hit compound. A highly divergent synthetic route was established and enabled the synthesis of various classes of 2-(trifluoromethyl)pyridin-4-amines providing deep structure-activity relationship (SAR) insights. Lead generation resulted in a highly active optimized compound possessing also good drug metabolism and pharmacokinetic (DMPK) properties. Furthermore, this compound showed in vivo target engagement in a murine lung infection model. Based on this lead compound, a medicinal chemistry-driven multiparameter optimization allowed for deeper insights into structure-activity relationship (SAR) and structure-property relationship (SPR). In the course of this thesis, several compounds were synthesized with improved activity, solubility and metabolic stability. In addition, compounds based on computer-aided drug design were synthesized.Pseudomonas aeruginosa, ein omnipräsentes Gramnegatives Bakterium zählt laut Weltgesundheitsorganisation (WHO) zu den klinisch relevantesten Pathogenen. Dieses opportunistische Pathogen ist in der Lage, Biofilme und Persisterzellen zu bilden, die eine Eradizierung erschweren und übliche Antibiotika Therapien ineffektiv werden lassen. Diese Faktoren unterliegen dem Pseudomonas Quinolone Signal (PQS) Quorum Sensing (QS) System, welches dabei ein attraktives Target zur Behandlung dar. Diese Arbeit beschreibt das Design und die Synthese von neuen PqsR inversen Agonisten, basierend auf einer bereits beschriebenen hit Verbindung. Eine hoch divergente Syntheseroute wurde dabei etabliert und ermöglichte die Synthese verschiedener Klassen von 2-(Trifluoromethyl)pyridin-4-aminen und lieferte tiefe Einblicke in die Struktur-Aktivitätsbeziehungen. Die Leitstruktur Generierung brachte eine hoch-aktive Verbindung hervor, die ebenso über gute pharmakokinetische Eigenschaften verfügte und in einem murinen Lungeninfektionsmodel in vivo target engagement zeigte. Ausgehend von dieser Leitstruktur lieferte eine medizinal-chemische Multiparameter-Optimierung tiefe Einblicke in Struktur-Aktivitätsbeziehungen und Struktur-Eigenschaftsbeziehungen. Im Zuge dieser Leitstruktur Optimierung wurden verschiedene Verbindungen mit verbesserter Aktivität, Löslichkeit und Stabilität synthetisiert. Darüber hinaus wurden Verbindungen basierend auf Computer-gestütztem Wirkstoffdesign synthetisiert.DZIF, HV

Role of aggressivity on reactivity and craving before and after cue exposure in recently detoxified alcoholics: Results from an experimental study

The role of aggressivity and cue exposure in induction of craving were investigated in a clinical setting. Thirty abstinent alcoholic patients were divided into a low and a high aggressive group based on scores on the physical aggression subscale of the Buss-Durkee Hostility Inventory and exposed to alcohol cues. Craving was measured by means of the Alcohol Craving Questionnaire (ACQ) and Visual Analogue Scales (VAS). Important findings are: (1) main effects of aggressivity on `emotionality', `purposefulness' and `expectancy' of ACQ were very significant; (2) on `drinking intention' and `craving for alcohol' of VAS, aggressivity and cue exposure showed a significant interaction; (3) the main effect of cue exposure on heart rate also reached a significance level of 0.007. The results were discussed in the context of the Classical, Operant Conditioning Theory, the Cognitive Craving Theory of Tiffany, Gilbert's STAR Model, and the Self-Medication Hypothesis Copyright (C) 2001 S. Karger AG, Basel

Effects of irritability on craving before and after cue exposure in abstinent alcoholic inpatients: Experimental data on subjective response and heart rate

Objective: Irritability is often linked with problem drinking. The aim of this study is to examine the possible influence of irritability on craving induced by a cue-exposure paradigm. Methods: 30 male abstinent alcoholic inpatients of the Psychiatric Hospital of Munich University, Germany gave answers to a series of personality questionnaires. Results of this study concerning the impact of aggressivity on craving for alcohol has recently been published. In this study, the subjects were subdivided into a low- and a high-irritable group based on their scores on the irritability subscale of the Buss-Durkee Hostility Inventory and were exposed to alcohol cues. Craving was measured by means of the Alcohol Craving Questionnaire (ACQ) and Visual Analogue Scales (VAS). The heart rate was also assessed throughout the whole process. ANCOVA for repeated measurement was employed to evaluate the data - irritability disposition as the between-subject factor and the experimental manipulation (absence vs. presence of alcohol cues) as the within-subject factor. Results: Major findings are: (1) main effects of irritability on `emotionality', `purposefulness', and `expectancy' of the ACQ as well as on `craving for alcohol' of the VAS were significant; (2) cue exposure also exerted a significant main effect on I craving for alcohol' of the VAS and on the heart rate after the presentation of alcohol cues; (3) on `compulsivity' of the ACQ and `intention to alcohol intake' of the VAS; there was a significant interaction between irritability and cue exposure. The high-irritable alcoholics, compared with their statements in the baseline, tended to report a higher control over alcohol intake and a lower intention to alcohol use after cue exposure. However, after confrontation with alcohol stimuli, their low-irritable counterparts reported a much lower control and a slightly higher intention than they did in the baseline. Conclusions: The results of this study indicate that induced craving in hospitalized alcohol addicts probably varies with the magnitude of their irritability; it might make patients more aware of their vulnerability to alcohol, help them develop more differential coping strategies and improve medical therapy against alcohol craving. Copyright (C) 2002 S. Karger AG, Basel

Germany's Defense Budget 2024: The Planned Increase Is Not Yet Enough

Germany's ruling coalition presented its draft of the 2024 federal budget at the beginning of July. This was preceded by months of wrangling to find a compromise between complying with its federal "debt brake" rule on the one hand and accommodating the diverse funding wishes of individual ministries on the other. Although Germany's defense budget was increased, that increase is still too low

Alcohol consumption in heroin users, methadone-substituted and codeine-substituted patients - Frequency and correlates of use

This retrospective study aims to determine whether there is a difference in the additional consumption of alcohol between addicts treated with methadone or dihydrocodeine (DHC) and untreated addicts injecting heroin. 1,685 patients admitted for opioid withdrawal between 1991 and 1997 were reviewed. Cross-reference tables and multiple logistic regression analyses were carried out. 28% of patients take more than 40 g of alcohol daily (on average 176 g). We found that patients who are treated with methadone or DHC drink alcohol significantly more often daily than the heroin-dependent patients (p<0.01). Using multiple regression analyses, the results were confirmed. Additionally, we found that co-abuse of alcohol was predicted by male gender, longer duration of drug use, additional daily consumption of tetrahydrocannabinol and daily consumption of benzodiazepines. Alcohol consumption by opioid-addicted patients treated with methadone or DHC presents a serious medical problem. Co-abuse of alcohol will receive more attention Copyright (C) 2003 S. Karger AG, Basel

Deterrence and Defense in Times of COVID-19: Europe’s Political Choices

Due to the COVID-19 pandemic, Europe is headed for a recession that will dwarf the economic downturn after the 2008 financial crisis. The impact on national defense sectors could be devastating. But as crisis and responses are still in the early stage, governments can still take measures to mitigate the effect on defense. To safeguard political and defense priorities, EU and NATO States need to act jointly and decisively