11 research outputs found
Report on a new opioid NPS : chemical and in vitro functional characterization of a structural isomer of the MT-45 derivative diphenpipenol
No full textIn this paper, the identification and full characterization of a novel non-fentanyl opioid sourced online, which is a member of the 1-substituted-4-(1,2-diphenylethyl)piperazine derivatives related to MT-45, is reported. The sample was sold under the name “diphenpipenol,” (3-[2-[4-(2-methoxyphenyl)piperazin-1-yl]-2-phenylethyl]phenol), although extensive NMR analysis showed that the product obtained was actually a diphenpipenol structural isomer, (2-[4-(2-methoxyphenyl)piperazin-1-yl]-1,2-diphenylethanol). Liquid chromatography time-of-flight mass spectrometry identified an exact mass for the protonated molecule of m/z 389.2264, with two prominent fragment ions (m/z 91.0567 and 150.0937), which were not reported in earlier literature describing MT-45 derivatives. The chemical characterization was finalized by gas chromatography–mass spectrometry, high-performance liquid chromatography diode array detector and Fourier-transform infrared spectroscopy analyses. This product is a clear example of the trend that new non-fentanyl opioids are reappearing on the recreational drug market to escape the recent changes in (inter)national legislation concerning fentanyl analogues. Although in this particular case, the product’s potency and efficacy were relatively low, other new non-fentanyl opioids might possess stronger potencies and therefore pose greater health risks for ignorant users. The fact that the product was sold under the wrong name further demonstrates the well-known problematic issue of a mismatch between the adverted and true identity, confirming the irregularities of the online new psychoactive substances market
2-((3,5-Dinitrobenzyl)thio)quinazolinones : potent antimycobacterial agents activated by deazaflavin (F420)-dependent nitroreductase (Ddn)
No full textSwapping the substituents in positions 2 and 4 of the previously synthesized but yet undisclosed 5-cyano-4-(methylthio)-2-arylpyrimidin-6-ones 4, ring closure, and further optimization led to the identification of the potent antitubercular 2-thio-substituted quinazolinone 26. Structure-activity relationship (SAR) studies indicated a crucial role for both meta-nitro substituents for antitubercular activity, while the introduction of polar substituents on the quinazolinone core allowed reduction of bovine serum albumin (BSA) binding (63c, 63d). While most of the tested quinazolinones exhibited no cytotoxicity against MRC-5, the most potent compound 26 was found to be mutagenic via the Ames test. This analogue exhibited moderate inhibitory potency against Mycobacterium tuberculosis thymidylate kinase, the target of the 3-cyanopyridones that lies at the basis of the current analogues, indicating that the whole-cell antimycobacterial activity of the present S-substituted thioquinazolinones is likely due to modulation of alternative or additional targets. Diminished antimycobacterial activity was observed against mutants affected in cofactor F-420 biosynthesis (fbiC), cofactor reduction (fgd), or deazaflavin-dependent nitroreductase activity rv3547 , indicating that reductive activation of the 3,5-dinitrobenzyl analogues is key to antimycobacterial activity
Distributed forms of school leadership: A critical and sociological analysis
No full textDistributed leadership is a free-floating concept that has come to prominence in the education field. Policy-makers, researchers and practitioners alike tout it as the mode of leadership suitable for twenty-first century schools. The quantity of commentary, related typologies, research and recognition in education policy gives the impression that distributed leadership is a mature concept. Most writers appear to assume that distributed leadership is beyond controversy, contributes to official legitimised school improvement and so is in no need of any re-theorising. The thesis in this study provides an alternative view. It argues that it is time to reject the grand narrative of distributed leadership and replace it with a critical and sociological re-theorising of distributed forms of leadership that reveal how authority and symbolic power co-exist in hybrid configurations of day-to-day leadership practice. In other words, the conceptual development of distributed leadership is at a pivotal point.
Two forms of analysis led to this rejection and re-theorising. One was in the broader school and generic leadership fields, while the other was on research in schools. The discussion in the first part of this study reveals that existent theorising and research of distributed leadership is predominantly silent around power, micropolitics, and the performative policies that have created environments conducive to distributed leadership being recommended as a ‘vehicle’ for reform. Most of the research to date can be categorised as either descriptive, with a tendency to be apolitical, or normative, with a tendency to oversimplify complexity. However, a critical analysis of related typologies and research suggests that there is a recent acknowledgment that distributed leadership exists in differing forms and is more complex than originally thought.
The school-based research in part two of this study was a commitment to understand day-to-day leadership practice in situ over 20 months, in two New Zealand suburban secondary schools. This investigation confirmed that existing conceptualisations, normative research and commentary of distributed leadership tended to be over-simplified. The distributed forms of leadership that emerged in each school were unique, due to the different educative, social, political and historical contexts that shaped and re-shaped the differing forms over time. There was no one preferred way of understanding how leadership existed in distributed forms. Analysis of the case studies led to the development of an analytical framework that can help understand the complexity of distributed forms of leadership that schools rely on.
The third and final part focuses on the thesis of this study. It rejects the distributed leadership grand narrative and argues for a critical and sociological re-theorising, that incorporates symbolic capital, symbolic power and authority. The re-theorising illustrates how authoritative capital co-exists with human, cultural and social forms of capital to form organisational and emergent distributed forms of leadership in hybrid configurations. This leads to a satisfactory theorising of distributed forms of leadership that builds on the complexity recently acknowledged in the field and reflects the reality of day-to-day school leadership practice
Report on a novel emerging class of highly potent benzimidazole NPS opioids: chemical and in vitro functional characterization of isotonitazene
No full textThis paper reports on the identification and full chemical characterization of isotonitazene (N,N-diethyl-2-[5-nitro-2-({4-[(propan-2-yl)oxy]phenyl}methyl)-1H-benzimidazol-1-yl]ethan-1-amine), a potent NPS opioid and the first member of the benzimidazole class of compounds to be available on online markets. Interestingly, this compound was sold under the name etonitazene, a structural analog. Identification of isotonitazene was performed by gas chromatography mass spectrometry (GC-MS) and liquid chromatography time-of-flight mass spectrometry (LC-QTOF-MS), the latter identifying an exact-mass m/z value of 411.2398. All chromatographic data indicated the presence of a single, highly pure compound. Confirmation of the specific benzimidazole regio-isomer was performed using H-1 and C-13 NMR spectroscopy, after which the chemical characterization was finalized by recording Fourier-transform (FT-IR) spectra. A live cell-based reporter assay to assess the in vitro biological activity at the mu-opioid receptor (MOR) revealed that isotonitazene has a high potency (EC50 of 11.1 nM) and efficacy (E-max 180% of that of hydromorphone), thus confirming that this substance is a strong opioid. Isotonitazene has not been previously detected, either in powder form, or in biological fluids. The high potency and efficacy of isotonitazene, combined with the fact that this compound was being sold undiluted, represents an imminent danger to anyone aiming to use this powder
Positively selected modifications in the pore of TbAQP2 allow pentamidine to enter Trypanosoma brucei
No full textMutations in the Trypanosoma brucei aquaporin AQP2 are associated with resistance to pentamidine and melarsoprol. We show that TbAQP2 but not TbAQP3 was positively selected for increased pore size from a common ancestor aquaporin. We demonstrate that TbAQP2's unique architecture permits pentamidine permeation through its central pore and show how specific mutations in highly conserved motifs affect drug permeation. Introduction of key TbAQP2 amino acids into TbAQP3 renders the latter permeable to pentamidine. Molecular dynamics demonstrates that permeation by dicationic pentamidine is energetically favourable in TbAQP2, driven by the membrane potential, although aquaporins are normally strictly impermeable for ionic species. We also identify the structural determinants that make pentamidine a permeant although most other diamidine drugs are excluded. Our results have wide-ranging implications for optimising antitrypanosomal drugs and averting cross-resistance. Moreover, these new insights in aquaporin permeation may allow the pharmacological exploitation of other members of this ubiquitous gene family
Structure-aided optimization of non-nucleoside M. tuberculosis thymidylate kinase inhibitors
No full textMycobacterium tuberculosis thymidylate kinase (MtTMPK) has emerged as an attractive target for rational drug design. We recently investigated new families of non-nucleoside MtTMPK inhibitors in an effort to diversify MtTMPK inhibitor chemical space. We here report a new series of MtTMPK inhibitors by combining the Topliss scheme with rational drug design approaches, fueled by two co-crystal structures of MtTMPK in complex with developed inhibitors. These efforts furnished the most potent MtTMPK inhibitors in our assay, with two analogues displaying low micromolar MIC values against H37Rv Mtb. Prepared inhibitors address new sub-sites in the MtTMPK nucleotide binding pocket, thereby offering new insights into its druggability. We studied the role of efflux pumps as well as the impact of cell wall permeabilizers for selected compounds to potentially provide an explanation for the lack of correlation between potent enzyme inhibition and whole-cell activity. © 2021 Elsevier Masson SA
Phenotypic Evaluation of Nucleoside Analogues against Trypanosoma cruzi Infection: In Vitro and In Vivo Approaches
No full textChagas disease, caused by Trypanosoma cruzi (T. cruzi), is a serious public health problem. Current treatment is restricted to two drugs, benznidazole and nifurtimox, displaying serious efficacy and safety drawbacks. Nucleoside analogues represent a promising alternative as protozoans do not biosynthesize purines and rely on purine salvage from the hosts. Protozoan transporters often present different substrate specificities from mammalian transporters, justifying the exploration of nucleoside analogues as therapeutic agents. Previous reports identified nucleosides with potent trypanocidal activity; therefore, two 7-derivatized tubercidins (FH11706, FH10714) and a 3′-deoxytubercidin (FH8513) were assayed against T. cruzi. They were highly potent and selective, and the uptake of the tubercidin analogues appeared to be mediated by the nucleoside transporter TcrNT2. At 10 μM, the analogues reduced parasitemia >90% in 2D and 3D cardiac cultures. The washout assays showed that FH10714 sterilized the infected cultures. Given orally, the compounds did not induce noticeable mouse toxicity (50 mg/kg), suppressed the parasitemia of T. cruzi-infected Swiss mice (25 mg/kg, 5 days) and presented DNA amplification below the limit of detection. These findings justify further studies with longer treatment regimens, as well as evaluations in combination with nitro drugs, aiming to identify more effective and safer therapies for Chagas disease
Discovery and development of an advanced lead for the treatment of African trypanosomiasis
No full textAfrican trypanosomiasis is a widespread disease of human and veterinary importance caused by various Trypanosoma spp. with a globally devastating impact and a need for novel treatment options. We here provide a comprehensive preclinical evaluation of nucleoside analogues, 6-thioether-modified tubercidins, with curative activity against African trypanosomiasis. Promising hits were identified following in vitro screening against the most relevant trypanosome species. Selected hit compounds were extensively tested for in vitro metabolic stability, potency in in vivo mouse models for the various species, genotoxicity in an in vitro testing battery, and mode of action studies (i.e., genome-wide RNA interference library screening and metabolomics). Among the nucleoside analogues, analogue 3 was curative in mouse models with no indication of genotoxicity and a low ecotoxicological footprint. Mode-of-action studies revealed that P1-type nucleoside transporters and adenosine kinase are involved in the uptake and activation, respectively. Analogue 3 represents a potent, advanced lead fitting the preferred target product profile for a broad-spectrum trypanocide regardless of the causative species
Positively selected modifications in the pore of TbAQP2 allow pentamidine to enter Trypanosoma brucei
No full textMutations in the Trypanosoma brucei aquaporin AQP2 are associated with resistance
to pentamidine and melarsoprol. We show that TbAQP2 but not TbAQP3 was positively selected
for increased pore size from a common ancestor aquaporin. We demonstrate that TbAQP2’s
unique architecture permits pentamidine permeation through its central pore and show how
specific mutations in highly conserved motifs affect drug permeation. Introduction of key TbAQP2
amino acids into TbAQP3 renders the latter permeable to pentamidine. Molecular dynamics
demonstrates that permeation by dicationic pentamidine is energetically favourable in TbAQP2,
driven by the membrane potential, although aquaporins are normally strictly impermeable for ionic
species. We also identify the structural determinants that make pentamidine a permeant although
most other diamidine drugs are excluded. Our results have wide-ranging implications for
optimising antitrypanosomal drugs and averting cross-resistance. Moreover, these new insights in
aquaporin permeation may allow the pharmacological exploitation of other members of this
ubiquitous gene family
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Effects of executive-level leader's transformational leadership on talent retention in post merger and acquisition in China
No full textTalent retention, which can be defined as organizational practices aiming at maintaining the continued employment of high potential and high-performing incumbents to fill the key positions that have the potential to have an impact on the competitive advantage of an organization (Schneider, 1987; Coldwell et al., 2008; Zhang et al., 2014), has been identified by previous researchers (e.g. Lubatkin et al., 1999; Cooke, 2006; Hartmann et al., 2010; Makela et al., 2010) as a particularly important measure of post-merger and acquisition (M&A) performance in contemporary M&A situations in multinational organizations. Connected to this, research (e.g. Bass, 1985; Bycio et al., 1995; Ya-Anan and Bunchapattanasukda, 2011; Zhang et al., 2014) has shown that transformational leadership can be one of the most important factors in predicting talent retention, but little research has been conducted to understand the underlying mechanisms through which transformational leadership may influence retention strategies in post-M&A performance. The aim of this DBA study is to address this research gap by examining whether and how executive-level leaders‘ transformational leadership style influences talent retention in a post-M&A Chinese context. Three research questions guide this DBA study. Firstly, to what extent does executive-level leaders‘ transformational leadership exert direct influence on post-M&A talent retention in mainland China? Secondly, to what extent does executive-level leader‘s transformational leadership exert indirect influence on post-M&A talent retention in mainland China? Thirdly, what factors mediate the influence of transformational leadership on talent retention and why? In the first stage of this doctoral study it was identified that transformational leadership can exert direct influence on talent retention without any mediator (Bass, 1985; Bycio et al., 1995; Ya-Anan and Bunchapattanasukda, 2011), and among factors that mediate the indirect influence of transformational leadership on talent retention, job satisfaction (Locke, 1976; Petty et al., 2005; Mallol et al., 2007; Smith et al., 2011) and organizational commitment (Price and Mueller, 1981; Hom and Kinicki, 2001; Brown and Yoshioka, 2003; Mallol et al., 2007) are recognized by previous researchers as the most important two. A conceptual framework was therefore presented describing the relations of key variables. Allied to this 8 framework, and arising from the theoretical arguments for transf ormational leadership‘s influence on talent retention, are six propositions. To test these propositions and explain the associations among variables in the conceptual framework, a Chinese local company (known here as ‘FB’) located in Shenzhen city, acquired by a multinational corporation (known here as ‘FA’) in 2008, was chosen as the central study for this investigation as they have experienced post-M&A integration. A multi-method approach was taken to data collection and analysis. In the first phase, a fully-structured questionnaire was sent to 54 current employees recognized by the case company as talent, based on their performance, potential, and position. Correlation analysis and structural equation modeling enabled the relationship among variables to be examined. In the second phase, analysis of nine semi-structured interviews with talent was undertaken to map the relationships between different variables. Following this, a short, informal interview with the President of FB was conducted to gain information about his leadership style and FB‘s retention strategies. Results of this DBA study not only prove all six propositions but also indicate significant causal relationship among variables. Findings show that there are four approaches through which transformational leadership can influence talent retention: Transformational leadership directly exerts positive influence on talent retention. Transformational leadership‘s positive influence on talent retention can be mediated by job satisfaction of talent. Transformational leadership‘s positive influence on talent retention can be mediated by organizational commitment of talent. Transformational leadership‘s positive influence on talent retention can be mediated firstly by job satisfaction, and then by organizational commitment of talent. Results from survey and interviews indicate that executive-level leaders‘ transformational leadership style, especially their attributed charisma, idealized influence, and inspirational motivation, can directly exert positive influence on talent retention in the post-M&A Chinese context. Transformational leaders can also increase the rate of post-M&A talent retention through enhancing talent‘s satisfaction with regard to the job itself, learning and development opportunities, and some external job factors such as supervisor and co-worker relationship, organizational culture, and effectiveness of communication and working flow, or through enhancing talent‘s affective commitment. This DBA study contributes to the literature in several ways. Firstly, despite a significant degree of academic and practical interest, the topic of talent management remains under-investigated (Collings and Mellahi, 2009; Iles et al., 2010a; Zhang et al., 2014). This study increases this body of knowledge by defining talent and identifying critical factors that may affect the propensity of an individual to remain with or leave an organization. Furthermore, as Bass indicates in his works (1985; 1998), transformational leadership can be one of the most important factors to control talent turnover. However, although such association has been studied, it is surprising that little research has been conducted to understand the underlying mechanisms through which transformational leadership exerts its influence on talent retention. This study contributes an empirically-supported theoretical framework for relationships between transformational leadership and talent retention by describing four approaches through which transformational leadership can influence talent retention. It also contributes to this line of studies by recognizing transformational leadership‘s superior effectiveness in increasing the rate of talent retention over other leadership styles such as transactional and laissez-faire in Avolio and Bass‘ (1991) Full Range of Leadership Model. With regard to lessons for managerial practice, this DBA study recognizes the important role of executive-level leaders on talent retention strategies in the post -M&A context. Furthermore, although talent retention has been studied extensively in a western context, there are few studies addressing these issues with regard to Chinese companies (Cooke, 2008; Zhang et al., 2014). By using a case from mainland China, this study attempts to provide strategic guidance for multinational M&A practitioners who seek to increase their company’s rate of talent retention in the Chinese context. In addition, only a limited number of studies examine the underlying relationship between leadership styles and talent retention have been carried out in such a dynamic and unstable environment as post-M&A integration. Finally, the study attempts to provide a guidance for post-M&A executive-level leaders to adopt a suitable leadership style, or for multinational firms to select ‘the right leader’ for their acquisitions
