Automated synthesis and evaluation of potential new anti-microbial agents

A series of N1-benzylideneheteroarylcarboxamidrazones was prepared in an automated fashion, and tested against Mycobacterium fortuitum in a rapid screen for antimycobacterial activity. Many of the compounds from this series were also tested against Mycobacterium tuberculosis, and the usefulness as M.fortuitum as a rapid, initial screen for anti-tubercular activity evaluated. Various deletions were made to the N1-benzylideneheteroarylcarboxamidrazone structure in order to establish the minimum structural requirements for activity. The N1-benzylideneheteroarylcarbox-amidrazones were then subjected to molecular modelling studies and their activities against M.fortuitum and M.tuberculosis were analysed using quantitative structure-analysis relationship (QSAR) techniques in the computational package TSAR (Oxford Molecular Ltd.). A set of equations predictive of antimycobacterial activity was hereby obtained. The series of N1-benzylidenehetero-arylcarboxamidrazones was also tested against a multidrug-resistant strain of Staphylococcus aureus (MRSA), followed by a panel of Gram-positive and Gram-negative bacteria, if activity was observed for MRSA. A set of antimycobacterial N1-benzylideneheteroarylcarboxamidrazones was hereby discovered, the best of which had MICs against m. fortuitum in the range 4-8μgml-1 and displayed 94% inhibition of M.tuberculosis at a concentration of 6.25μgml-1. The antimycobacterial activity of these compounds appeared to be specific, since the same compounds were shown to be inactive against other classes of organisms. Compounds which were found to be sufficiently active in any screen were also tested for their toxicity against human mononuclear leucocytes. Polyethylene glycol (PEG) was used as a soluble polymeric support for the synthesis of some fatty acid derivatives, containing an isoxazoline group, which may inhibit mycolic acid synthesis in mycobacteria. Both the PEG-bound products and the cleaved, isolated products themselves were tested against M.fortuitum and some low levels of antimycobacterial activity were observed, which may serve as lead compounds for further studies.

Design and synthesis of potential antimicrobial agents

Tuberculosis is one of the most devastating diseases in the world primarily due to several decades of neglect and an emergence of multidrug-resitance strains (MDR) of M. tuberculosis together with the increased incidence of disseminated infections produced by other mycobacterium in AIDS patients. This has prompted the search for new antimycobacterial drugs. A series of pyridine-2-, pyridine-3-, pyridine-4-, pyrazine and quinoline-2-carboxamidrazone derivatives and new classes of carboxamidrazone were prepared in an automated fashion and by traditional synthesis. Over nine hundred synthesized compounds were screened for their anti mycobacterial activity against M. fortutium (NGTG 10394) as a surrogate for M. tuberculosis. The new classes of amidrazones were also screened against tuberculosis H37 Rv and antimicrobial activities against various bacteria. Fifteen tested compounds were found to provide 90-100% inhibition of mycobacterium growth of M. tuberculosis H37 Rv in the primary screen at 6.25 μg mL-1. The most active compound in the carboxamidrazone amide series had an MIG value of 0.1-2 μg mL-1 against M. fortutium. The enzyme dihydrofolate reductase (DHFR) has been a drug-design target for decades. Blocking of the enzymatic activity of DHFR is a key element in the treatment of many diseases, including cancer, bacterial and protozoal infection. The x-ray structure of DHFR from M. tuberculosis and human DHFR were found to have differences in substrate binding site. The presence of glycerol molecule in the Xray structure from M. tuberculosis DHFR provided opportunity to design new antifolates. The new antifolates described herein were designed to retain the pharmcophore of pyrimethamine (2,4- diamino-5(4-chlorophenyl)-6-ethylpyrimidine), but encompassing a range of polar groups that might interact with the M. tuberculosis DHFR glycerol binding pockets. Finally, the research described in this thesis contributes to the preparation of molecularly imprinted polymers for the recognition of 2,4-diaminopyrimidine for the binding the target. The formation of hydrogen bonding between the model functional monomer 5-(4-tert-butyl-benzylidene)-pyrimidine-2,4,6-trione and 2,4-diaminopyrimidine in the pre-polymerisation stage was verified by 1H-NMR studies. Having proven that 2,4-diaminopyrimidine interacts strongly with the model 5-(4-tert-butylbenzylidene)- pyrimidine-2,4,6-trione, 2,4-diaminopyrimidine-imprinted polymers were prepared using a novel cyclobarbital derived functional monomer, acrylic acid 4-(2,4,6-trioxo-tetrahydro-pyrimidin-5- ylidenemethyl)phenyl ester, capable of multiple hydrogen bond formation with the 2,4- diaminopyrimidine. The recognition property of the respective polymers toward the template and other test compounds was evaluated by fluorescence. The results demonstrate that the polymers showed dose dependent enhancement of fluorescence emissions. In addition, the results also indicate that synthesized MIPs have higher 2,4-diaminopyrimidine binding ability as compared with corresponding non-imprinting polymers.

Introduction

Werner Sombart (1863-1941) was a famous and controversial social scientist in Germany during the early 20th century. Highly influential, his work and reputation have been indelibly tainted by his embrace of National Socialism in the last decade of his life. Although Sombart left an enormous opus spanning disciplinary boundaries, the scholarly assessment of and intellectual reaction to his work inside and outside of Germany is divided, and ambivalent. Best known for his analyses of capitalism - his essay "Why is There No Socialism in the United States?" remains a classic - Sombart consistently responded to the social and political developments that have shaped the 20th century. This collection provides a representative sampling of those portions of Sombart's work that have stood the test of time. The volume opens with a substantial introduction by the editors reviewing Sombart's life and career, the evolution of his major intellectual concerns, his relation to Marx and Weber, and his political affiliation with the Nazis. Their selection of texts emphasizes areas of his economic and cultural thought that remain relevant to intellectual trends in the social sciences, particularly those trends that seek a more broadly based, cross-disciplinary approach to the relationship of culture and economics. Sombart's writings on capitalism are represented by essays on the nature and origin of the market system and the diversity of its actors and motives among the bourgeoisie and the proletariat. Also included is an excerpt from Sombart's controversial volume "The Jews and Modern Capitalism" exploring the widely perceived relation between economic life and Judaism as a religion. In essays on the economics of cultural processes, Sombart's comprehensive and expansive idea of cultural science yields remarkable and prophetic insights into the nature of urbanism, luxury consumption, fashion and the cultural secularization of love. The volume's final section consists of Sombart's reflections on the social influences of technology, the economic life of the future, and on socialism, including the influential essay "Why is There No Socialism in the United States?". Encapsulating the most valuable aspects of his work, this study provides clear demonstration of Sombart's sense for fine cultural distinctions and broad cultural developments and the predictive power of his analyses. It should be of interest to sociologists, economists, political scientists and specialists in cultural studies.

Economic life in the modern age

Werner Sombart (1863-1941) may well have been the most famous and controversial social scientist in Germany during the early twentieth century. Highly influential, his work and reputation have been indelibly tainted by his embrace of National Socialism in the last decade of his life. Although Sombart left an enormous opus spanning disciplinary boundaries, intellectual reaction to his work inside and outside of Germany is divided and ambivalent. Sombart consistently responded to the social and political developments that have shaped the twentieth century. Economic Life in the Modern Age provides a representative sampling of those portions of Sombart's work that have stood the test of time. The volume opens with a substantial introduction reviewing Sombart's life and career, the evolution of his major intellectual concerns, his relation to Marx and Weber, and his political affiliation with the Nazis. The editors' selection of texts emphasizes areas of Sombart's economic and cultural thought that remain relevant, particularly to those intellectual trends that seek a more broadly based, cross-disciplinary approach to culture and economics. Sombart's writings on capitalism are represented by essays on the nature and origin of the market system and the diversity of motives among the bourgeoisie and the proletariat. Also included is an excerpt from Sombart's controversial The Jews and Modern Capitalism, exploring the widely perceived relation between economic life and Judaism as a religion. In essays on the economics of cultural processes, Sombart's comprehensive and expansive idea of cultural science yields prophetic insights into the nature of urbanism, luxury consumption, fashion, and the cultural secularization of love. The volume's final section consists of Sombart's reflections on the social influences of technology, the economic life of the future, and on socialism, including the influential essay "Why is there no Socialism in the United States." Encapsulating the most valuable aspects of his work, Economic Life in the Modern Age provides clear demonstration of Sombart's sense for fine cultural distinctions and broad cultural developments and the predictive power of his analyses. It will be of interest to sociologists, economists, political scientists, and specialists in cultural studies.

Brand equity and purchase intention in fashion industry:a cross-cultural study in Asia and Europe

This research is the leading brand for purchase of assets, and analyzing the factors based on brand asset components and the relationship between the brand and brand assets assets impact factors and purchase intent on uncovering the relationship between components and trademarks centered on South Korea and the United Kingdom, by comparing the asset management plan would generate. The study, information navigation product knowledge affects of constant (+), brand attitudes and knowledge of the brand loyalty and brand value to the constant trademark (+). Brand value and brand loyalty and purchase intent-(+) in the United Kingdom, on the other hand, of the impact that do not affect that.

Design and designing:a critical introduction

Design and Designing provides a broad and critical understanding of what is essentially a practical subject. Designing today is less a craft and more a part of the knowledge economy. It's all about knowing how to acquire knowledge and how to apply it creatively. Design and Designing covers the design process, modelling and drawing, working with clients, production and consumption, sustainability, professional practice and design futures. Chapters are written by expert teachers and practitioners from around the globe, each presenting an accessible and engaging overview of their field of design. Every chapter is highly illustrated with a combination of images and information boxes, which extend or highlight key material. Each section concludes with a design project, a hands-on activity for the reader. Design and Designing covers the full spectrum of design types, from graphic communication to product design, from fashion to games design, setting every type in its aesthetic, ethical and social contexts. With this essential book, readers will learn from today's best practice and best thinking in design, they will develop a critical sense, and become the designers of tomorrow.

Encouraging the intellectual craft of living research:tattoos, theory and time

This chapter contributes to the anthology on learning to research - researching to learn because it emphases a need to design curricula that enables living research, and on-going researcher development, rather than one that restricts student and staff activities, within a marketised approach towards time. In recent decades higher education (HE) has come to be valued for its contribution to the global economy. Referred to as the neo-liberal university, a strong prioritisation has been placed on meeting the needs of industry by providing a better workforce. This perspective emphasises the role of a degree in HE to secure future material affluence, rather than to study as an on-going investment in the self (Molesworth , Nixon & Scullion, 2009: 280). Students are treated primarily as consumers in this model, where through their tuition fees they purchase a product, rather than benefit from the transformative potential university education offers for the whole of life.Given that HE is now measured by the numbers of students it attracts, and later places into well-paid jobs, there is an intense pressure on time, which has led to a method where the learning experiences of students are broken down into discrete modules. Whilst this provides consistency, students can come to view research processes in a fragmented way within the modular system. Topics are presented chronologically, week-by-week and students simply complete a set of tasks to ‘have a degree’, rather than to ‘be learners’ (Molesworth , Nixon & Scullion, 2009: 277) who are living their research, in relation to their own past, present and future. The idea of living research in this context is my own adaptation of an approach suggested by C. Wright Mills (1959) in The Sociological Imagination. Mills advises that successful scholars do not split their work from the rest of their lives, but treat scholarship as a choice of how to live, as well as a choice of career. The marketised slant in HE thus creates a tension firstly, for students who are learning to research. Mills would encourage them to be creative, not instrumental, in their use of time, yet they are journeying through a system that is structured for a swift progression towards a high paid job, rather than crafted for reflexive inquiry, that transforms their understanding throughout life. Many universities are placing a strong focus on discrete skills for student employability, but I suggest that embedding the transformative skills emphasised by Mills empowers students and builds their confidence to help them make connections that aid their employability. Secondly, the marketised approach creates a problem for staff designing the curriculum, if students do not easily make links across time over their years of study and whole programmes. By researching to learn, staff can discover new methods to apply in their design of the curriculum, to help students make important and creative connections across their programmes of study.