Dissertations / Theses: 'Antibiotic synthesis/chemistry'

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Mason, Ian. "The biomimetic synthesis of polyether antibiotic fragments." Thesis, University of Cambridge, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.235930.

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The asymmetric synthesis of the C₁₃-C₂₇ moiety 44 of the polyether antibiotic etheromycin is described. The final step in the synthesis was the formation of the tricyclic fragment 44 by a biomimetic triepoxide cyclisation cascade. The cyclisation cascade, 144 to 44, is stereospecific and entirely dependent upon the epoxides stereochemistry. The absolute stereochemistry of each of the three epoxides was independently controlled by the Sharpless asymmetric epoxidation methodology. The carbon skeleton of 44 was constructed from geraniol, (R)-methyl 3-hydroxy-2-methylpropionate 117, and two units of t-butyl acetate. Apart from C₂₆, the chiral centres were all controlled by the Sharpless asymmetric epoxidation. The synthetic strategy was designed to effect the stepwise enantioselective introduction of the three epoxides while building the C₁₃-C₂₇ carbon skeleton, and directing a subsequent cascade reaction by an internal nucleophile. Two trisubstituted epoxides were introduced stepwise with >20:1 stereoselectivity by asymmetric epoxidation of a geraniol derived segment. The fragment was manipulated between epoxidations to allow stepwise introduction of the epoxides, and to ensure terminal differentiation of the groups. Both hydroxyl groups used to control epoxidation were subsequently and separately utilised, after conversion to the iodide, in alkyation reactions with the lithium enolate of t-butyl acetate to extend the carbon chain. No other conditions investigated to selectively react α to epoxides were satisfactory. Of the two t-butyl ester groups introduced, one (C_24) was reduced to the aldehyde and coupled in a Julia reaction with a sulphone derived from 117. The resulting trans olefin was converted into a trans homoallylic alcohol, which was epoxidised by Sharpless methodology with 3 : 1 stereoselectivity. The second of the t-butyl esters (C_13) was used as an internal nucleophile to induce the cascade reaction. The natural ring stereochemistry of 44 was assumed from the high predictability and stereocontrol of the epoxidation reactions and confirmed by ^1H NMR nOe difference experiments. The synthesis of the sulphone 161, in which the three contiguous chiral centres and methyl ketone represents a common polyether terminus, was also demonstrated using a stereocontrolled aldol reaction.

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Hill, M. L. "Synthesis of the antiviral antibiotic virantmycin." Thesis, University of Cambridge, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.373683.

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Casey, Lorraine A. "The synthesis of potential enzyme inhibitors." Thesis, University of Huddersfield, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.290421.

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Kang, T. W. "Novel synthesis of #beta#-lactams via radical pathways." Thesis, University of Oxford, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.379970.

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5

Glassford, Ian Michael. "Addressing Antibiotic Resistance: The Discovery of Novel Ketolide Antibiotics Through Structure Based Design and In Situ Click Chemistry." Diss., Temple University Libraries, 2016. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/410231.

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Chemistry
Ph.D.
Antibiotic resistance has become and will continue to be a major medical issue of the 21st century. If not addressed, the potential for a post-antibiotic era could become a reality, one that the world has not been familiar with since the early 1900’s. Multidrug-resistant hospital-acquired bacterial infections already account for close to 2 million cases and 23,000 deaths in the United States, along with 20 billion dollars of additional medical spending each year. The CDC released a report in 2013 regarding the seriousness of antibiotic resistance and providing a snapshot of costs and mortality rates of the most serious antibiotic resistant bacteria, which includes 17 drug resistant bacteria, such as carbapenem-resistant Enterobacteriaceae, vancomycin-resistant Enterococcus and Staphylococcus aureus, and multidrug-resistant Acinetobacter and Pseudomonas aeruginosa. The development of antibiotic resistance is part of bacteria’s normal evolutionary process and thus impossible to completely stop. To ensure a future where resistant bacteria do not run rampant throughout society, there is a great need for new antibiotics and accordingly, methods to facilitate their discovery Macrolides are a class of antibiotics that target the bacterial ribosome. Since their discovery in the 1950’s medicinal chemistry has created semi-synthetic analogues of natural product macrolides to address poor pharmacokinetics and resistance. Modern X-Ray crystallography has allowed the chemist access to high resolution images of the bacterial ribosome bound to antibiotics including macrolides which has ushered in an era of structure-based design of novel antibiotics. These crystal structures suggest that the C-4 methyl group of third generation ketolide antibiotic telithromycin can sterically clash with a mutated rRNA residue causing loss of binding and providing a structural basis for resistance. The Andrade lab hypothesized that the replacement of this methyl group with hydrogen would alleviate the steric clash and allow the antibiotic to retain activity. To this end, the Andrade lab set out on a synthetic program to synthesize four desmethyl analogues of telithromycin by total synthesis that would directly test the steric clash hypothesis and also provide structure-activity relationships about these methyl groups which have not been assessed in the past. Following will contain highlights of the total synthesis of (-)-4,8,10-didesmethyl telithromycin, (-)-4,10-didesmethyl telithromycin, and (-)-4,8-desmethyl telithromycin and my journey toward the total synthesis of (-)-4-desmethyl telithromycin Traditional combinatorial chemistry uses chemical synthesis to make all possible molecules from various fragments. These molecules then need to be purified, characterized, and tested against the biological target of interest. While high-throughput assay technologies (i.e., automation) has streamlined this process to some extent, the process remains expensive when considering the costs of labor, reagents, and solvent to synthesize, purify, and characterize all library members. Unlike traditional combinatorial chemistry, in situ click chemistry directly employs the macromolecular target to template and synthesize its own inhibitor. In situ click chemistry makes use of the Huisgen cycloaddition of alkyne and azides to form 1,2,3-triazoles, which normally reacts slowly at room temperature in the absence of a catalyst. If azide and alkyne pairs can come together in a target binding pocket the activation energy of the reaction can be lowered and products detected by LC-MS. Compounds found in this way generally show tighter binding than the individual fragments. Described in the second part of this dissertation is the development of the first in situ click methodology targeting the bacterial ribosome. Using the triazole containing third generation ketolide solithromycin as a template we were able to successfully show that in situ click chemistry was able to predict the tightest binding compounds.
Temple University--Theses

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Ashcroft, Neil David. "Towards a total synthesis of the ansamycin antibiotic herbimycin A." Thesis, University of Reading, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.294580.

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Khatri, Hem Raj. "Synthesis of Complex ortho-Allyliodoarenes via Reductive Iodonio-Claisen Rearrangement and Total Synthesis of Antitumor Antibiotic Derhodinosylurdamycin A." University of Toledo / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1431342601.

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8

Chambers, Christopher Steven. "The synthesis of novel analogues of the antitumour antibiotic pyrrolobenzodiazepines." Thesis, University of Huddersfield, 2009. http://eprints.hud.ac.uk/id/eprint/7068/.

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In this thesis, the novel synthesis of tetra- and triazolo-analogues of the pyrrolobenzodiazepines, pyrrolobenzothiadiazepines, benzodiazepines and benzothiadiazepines are described. These compounds are of great interest as synthetic targets due to their potential medical properties. The key processes are the intramolecular 1,3-dipolar cycloaddition between the azide and the nitrile present in compound (1), the azide and the alkyne present in compound (2) the azide and the alkene present in compound (3), to form the novel final compounds of type (4). The synthesis of these precursors from readily available starting materials is discussed. The intramolecular 1,3-dipolar cycloaddition of the alkene with the azide (3) afforded the triazoline(4, Z = CH2) which upon nitrogen extrusion formed either the methyl imine (5) or an aziridine (6) as shown in the Scheme on the next page. Reactions of other alkenes, more highly substituted than compound (3) are also described. This thesis will also describe a general route to triazolobenzodiazepines and triazolobenzothiadiazepines (7, X = CO, SO2; Z = CH). The reactions of the corresponding nitriles (7, X = CO, SO2; Z = N) will also be described, as with other approaches to the pyrrolobenzodiazepines.

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Gavva, Shravan. "Single Step Synthesis of Antibiotic Kanamycin Embedded Gold Nanoparticles for Efficient Antibacterial Activity." TopSCHOLAR®, 2013. http://digitalcommons.wku.edu/theses/1282.

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Nanotechnology has become the most advanced type of drug delivery system within the last decade. This advancement shifted the focus on small carriers to increase the efficiency of the drugs. Among these, gold nanoparticles (GNPs) were found to have profound biomedical applications. In current research, kanamycin embedded GNPs were prepared in a single step, single phase, and bio-friendly (green synthesis) procedure. The synthesized Kanamycin-GNPs (Kan-GNPs) were spherical in shape and had a size range of 15 ± 3 nm. The chosen kanamycin is an aminoglycosidic antibiotic that is isolated from Streptomyces kanamyceticus. These special antibiotic GNPs are further characterized using several analytical methods like Transmission Electron Microscopy (TEM), Energy Dispersive Spectroscopy (EDS), Fourier Transform Infrared Spectroscopy (FTIR), and Ultra-Voilet/Visible spectroscopy (UV/Vis spectroscopy). The following research is a direct bio-friendly embedment of an antibiotic agent on the surface of the GNPs without any secondary capping agent or surface modification procedures.

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Waghwani, Hitesh Kumar. "One-Step Synthesis of Kanamycin Functionalized Gold Nanoparticles With Potent Antibacterial Activity Against Resistant Bacterial Strains." TopSCHOLAR®, 2015. http://digitalcommons.wku.edu/theses/1455.

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On the verge of entering the post-antibiotic era, numerous efforts are in place to regain the losing potential of antibiotics which are proving ineffective against common bacterial infections. Engineered nanomaterials, especially gold nanoparticles (GNPs) capped with antibacterial agents are proving to be an effective and novel strategy against multi-drug resistant (MDR) bacteria. In this study, we report a one-step synthesis of kanamycin-capped GNPs (20 ± 5 nm) utilizing the combined reducing and capping ability of the aminoglycoside antibiotic, kanamycin. Antibacterial assays showed dosedependent broad spectrum activity of Kan-GNPs against Gram-positive (Staphylococcus epidermidis and Enterococcus durans), Gram-negative (Escherichia coli and Enterobacter aerogenes) and Kan-resistant and MDR bacterial strains. A significant reduction in the minimum inhibitory concentration (MIC) of Kan-GNPs was observed as compared to free kanamycin against all the sensitive and resistant bacterial strains tested. Mechanistic studies using TEM and fluorescence microscopy showed that Kan- GNPs exerted their bactericidal action through disrupting the cellular membrane resulting in leakage of cytoplasmic content and death of bacterial cells. Results of this study provide a novel method in the development of antibiotic capped GNPs as potent next-generation antibacterial agents.

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Okamoto, Akimitsu. "Design, Synthesis and Evaluation of Novel DNA Alkylating Agents Based on the Chemistry of Antibiotic Kapurimycin A[3]." Kyoto University, 1998. http://hdl.handle.net/2433/157035.

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本文データは平成22年度国立国会図書館の学位論文(博士)のデジタル化実施により作成された画像ファイルを基にpdf変換したものである
Kyoto University (京都大学)
0048
新制・課程博士
博士(工学)
甲第7368号
工博第1743号
新制||工||1110(附属図書館)
UT51-98-G297
京都大学大学院工学研究科合成・生物化学専攻
(主査)教授齋藤烈, 教授吉田潤一, 教授伊藤嘉彦
学位規則第4条第1項該当

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Wasuna, Antonina. "Repositioning fusidic acid for tuberculosis: semi-synthesis of analogues and impact of mycobacterial biotransformation on antibiotic activity." Doctoral thesis, University of Cape Town, 2018. http://hdl.handle.net/11427/28154.

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Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is one of the leading causes of death globally, especially in low and middle-income countries. TB is primarily a curable disease, with chemotherapy predicated on a combination of four drugs. The increase in multiple forms of drug-resistant TB is a major cause for concern, underpinning the importance of a continuous pipeline of new anti-TB agents. Drug repositioning - that is, the optimization of existing drugs for new therapeutic indications - has shown promise in expanding the therapeutic options for TB chemotherapy. Fusidic acid (FA), a natural product-derived antibiotic, has modest in vitro antimycobacterial activity. Through a multi-disciplinary approach combining aspects of chemistry and biology, this study investigated the pharmacological and physicochemical properties of FA that might be exploited for optimization of FA as a lead compound for TB drug discovery. FA is a weak carboxylic acid, and it was hypothesised that the carboxylic acid moiety limits its permeation of the complex mycobacterial cell wall. Therefore, this study aimed to identify novel FA analogues with improved permeation properties and designed to act as potential prodrugs. By modifying the C-3 hydroxyl and the carboxylic acid moiety, alkyl and aminoquinoline derivatives were covalently fused to FA through ester and amide coupling reactions to generate hybrids and/or potential prodrugs.

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Heaviside, Elizabeth Anne. "Analogues of antibacterial natural products." Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:6b5bd771-515b-49d0-8ec9-cee115d3aebf.

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Analogues of Antibacterial Natural Products Elizabeth Anne Heaviside, St Catherine’s College, University of Oxford DPhil Thesis, Trinity Term 2012 This thesis is concerned with the synthesis and biological evaluation of structural mimics for the natural products 16-methyloxazolomycin and lemonomycin which display potent biological activity including antibacterial and antitumour activity. Chapter 1 explores methods and approaches to the discovery of new antibacterial drugs and the challenges faced in this respect. It also gives an overview of the properties of the natural products investigated in the following chapters and summarises previous synthetic approaches to these molecules published in the scientific literature. Chapter 2 describes the work carried out towards the synthesis of the diazabicyclo[3.2.1]octane unit of the tetrahydroisoquinoline antitumour antibiotic lemonomycin. The intended retrosynthesis of the natural product led to a 2,5-disubstituted pyrrolidine bearing a 1ʹ-amino functional group; a series of routes were explored for the synthesis of this unit. Using (S)-pyroglutamic acid, strategies using Eschenmoser and thiolactim ether coupling reactions were investigated. A sequence based on the formation of a pyrrolidine ring from the cyclisation of an appropriately substituted oxime ether derived from L-phenylalanine was then implemented but a competing Beckmann rearrangement/Grob fragmentation prevented access to the desired heterocycle. Preliminary investigations were also carried out on the modification of cyclic imines derived from oxime ethers which did not undergo Beckmann rearrangement. Chapter 3 describes the synthesis of a library of densely functionalised tetramic acid and pyroglutamate mimics for the right-hand fragment of 16-methyloxazolomycin, and their coupling with a gem-dimethylamide unit mimicking the middle fragment of the natural product. Tetramates were accessed through the Dieckmann cyclisation of N-acyloxazolidines and were derivatised with various alkyl halides. The pyroglutamates were accessed via the highly diastereoselective aldol cyclisation of N-acyloxazolidines formed by the amide coupling of a threonine derived oxazolidine and β-keto-acids. A series of β-keto-acids were synthesised through the acylation and subsequent ring-opening/decarboxylation reaction of Meldrum’s acid. The formation of right-hand/middle fragment adducts was explored using cycloaddition, alkylation and Sonogashira chemistry before a Wittig protocol led to the formation of adducts (E)- and (Z)- 402 and 403. Biological evaluation of the compounds synthesised in this chapter was carried out using both broth and hole-plate bioassays and active compounds were identified. Of particular note was that the Wittig adducts displayed a higher level of activity against Gram-negative E. coli than either the pyroglutamate or amide motifs alone.

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Panduwawala, Tharindi. "Natural product guided antibacterial drug discovery : tetramates as core scaffolds." Thesis, University of Oxford, 2016. https://ora.ox.ac.uk/objects/uuid:b507ca4d-ef35-4928-90a2-0a3f774a4ed2.

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This thesis describes the synthesis and biological evaluation of a library of compounds containing the tetramic acid core in search of novel antibacterial drug candidates. Chapter 1 discusses the need for new antibiotics due to the emergence of virulent bacterial strains resistant to clinically available drugs and the hiatus in the discovery of new replacement antibitoics that has become a global threat to human health. Different platforms for antibacterial drug discovery and the re-emergence of natural products-based approach that has gained importance in the quest for novel antibiotics are discussed. In this regard, the intrinsic antibacterial activity of natural products containing a tetramate core structure and the strategies developed to synthesise the core scaffold are described. Chapter 2 discusses the use of Ê-serine and Ê-cysteine in tetramic acid synthesis and the application of Ê-cysteine-derived thiazolidine templates suitable for stereoselective ring closing reactions to obtain the tetramic acid core with scope for further functionalization. Chapters 3 and 4 describe a range of synthetic routes for appropriate substitutions of the tetramate core for compound library generation. Elaboration of the tetramate core via carboxamide tetramate synthesis, Suzuki-Miyaura cross-coupling reactions, glycosylations and their aglycone analogue synthesis, etherification, tetramate-pyroglutamate systems, Buchwald aminations/amidations, cycloadditions and Î²-lactam hybrids as possible chemical modifications of the tetramate core structure are discussed. Chapter 5 describes the antibacetiral activity and physicochemical properties of the library of compounds synthesised. A preliminary evaluation of their antibiotic activity was conducted against S. aureus and E. coli using the hole-plate method. MICs of the tetramates synthesised were determined against several Gram-negative strains; Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Gram-positive strains; MRSA, Enterococcus faecalis and Streptococcus pneumoniae, in whole-cell bioassays. Physicochemical properties of the compound library were analysed to map the chemical space occupied by tetramates with potent antibacterial activity. Enzyme inhibition studies were conducted to identify possible modes of action that contribute to whole-cell antibiotic activity and in this regard, the inhibition of enzymes S. aureus topoisomerase IV, S. aureus RNA polymerase, E. coli RNA polymerase, E. coli gyrase and M. tuberculosis gyrase are discussed. Since plasma protein binding of compounds is an important factor that determines the bioavailability of antibiotics and their clinical outcome, a study of the binding affinity of these drug candidates to Human Serum Albumin (HSA) by both whole-cell bioassay and NMR spectroscopy-based protein binding experiments are discussed. Finally, a brief note on the potential of tetramic acids to function as proteasome inhibitors in anticancer chemotherapy is included at the end of this chapter.

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Kalu, Chimdi Eke. "Synthesis and Evaluation of 1,2,4-oxadiazolidinones: The Search for A Potential Non-β-lactam β-lactamase Inhibitors." Digital Commons @ East Tennessee State University, 2019. https://dc.etsu.edu/etd/3578.

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β-lactam antibiotics have been the most widely used drug of choice to combat infectious disease caused by bacteria. Unfortunately, their effectiveness is drastically threatened by bacterial β-lactamases. β-lactamases is responsible for the resistance to most antibiotic drugs. For decades, β-lactam β-lactamases inhibitors have been used to reduce bacterial resistance; however, in this study 1,2,4-oxadiazolidinone derivatives as a non-β-lactam β-lactamases inhibitor against TEM-1 and P99 β-lactamases. The significance of oxadiazolidinone is the prominent five-membered ring scaffold in its structure, which is configurationally stable and present in other biologically active compounds such as linezolid and avibactam. Oxadiazolidinones were synthesized by treating nitrones with isocyanates. The synthesized compounds were characterized using 1H and 13C NMR, GC-MS, and FTIR. Afterward, they were tested using Nitrocefin as substrate to determine their effectiveness against TEM-1 and P99 serine β-lactamase. Compound 2a-2c, and 3 showed inhibition ranging from 12-38%.

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Wang, Hua. "Semi-synthesis and biological evaluations of tunicamycin lipid analogues and investigation of the tunicamycin biosynthetic pathway." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:05c43287-9f84-45f4-8db4-0fb6c2763816.

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Tunicamycins are potent antimicrobial agents but are also toxic to mammalian cells, which render them clinically impractical to use to treat infectious diseases. Instead, they have been used extensively as biochemical tools to study the N-linked glycosylation of proteins. However, despite such a routine application, their inhibitory mechanisms are still not clear. The central objective of this thesis was to develop novel tunicamycin analogues that are non-toxic to eukaryotic cells that could serve as potential antimicrobial drug candidates. We hypothesised that if we retain the lipid character of tunicamycin structure and modify the GlcNAc moiety then the antimicrobial activity would be retained but the tunicamycins inhibitory action towards GPT would be abolished, thus diminishing tunicamycins cytotoxicity towards mammalian cells. I - Semi-synthesis of the Tunicamycin Core Scaffolds and Lipid Analogues Semi-synthetic strategies were devised for isolating tunicamycin core scaffolds and for the selective addition of lipid chains at the 10'-N and 2"-N positions of tunicamycin, yielding the first library of novel tunicamycin lipid analogues. II - Biological Evaluations of the Tunicamycin Core Scaffolds and Lipid Analogues For the first time, the antibacterial activity of tunicamycins was shown to be dependent on the presence of a lipid chain. The tunicamycin core scaffolds were shown to lack antibacterial activity and cytotoxicity. More importantly, the library of tunicamycin lipid analogues with lipid chain length from seven to twelve carbons showed titrated antibacterial activity profile. Furthermore, the tunicamycin lipid analogues were not only found to have potent antibacterial and anti-M. tuberculosis activities but were non-cytotoxic compared to tunicamycins. The relative therapeutic index calculated for the tunicamycin lipid analogues was up to several thousand folds more than tunicamycins. III - Investigation of the tunB and tunF Knockout in the tun Gene Cluster The tunB and tunF single knockout mutations were made in the tun gene cluster by PCR-targeting and then heterologously expressed in S. coelicolor. The tunB knockout successfully abolished tunicamycin biosynthesis and showed evidence by MS the first existence of exo-glycal intermediates in sugar biology, further supporting the discovery of TunA as a novel NDP-sugar 5,6-dehydrogenase. IV - Investigation of the TunD and TunE Enzymatic Activities in Tunicamycin Biosynthetic Pathway The recapitulation of TunD glycosyltransferase and TunE deacetylase activities in vitro were attempted. Recombinant TunD was refolded from insoluble TunD inclusion bodies, while TunE was isolated in small quantities. However, no TunD and TunE activities were found using proposed intermediates. The co-translation of the tun gene cluster and the formation of multi-protein complex are proposed to be involved in the tunicamycin biosynthesis.

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Wyszynski, Filip Jan. "Dissecting tunicamycin biosynthesis : a potent carbohydrate processing enzyme inhibitor." Thesis, University of Oxford, 2010. http://ora.ox.ac.uk/objects/uuid:3a7a509d-dba0-4d5b-9a39-a883c872d758.

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Tunicamycin nucleoside antibiotics were the first known to target the formation of peptidoglycan precursor lipid I in bacterial cell wall biosynthesis. They have also been used extensively as inhibitors of protein N-glycosylation in eukaryotes, blocking the biogenesis of early intermediate dolichyl-pyrophosphoryl-N-acetylglucosamine. Despite their unusual structures and useful biological properties, little is known about their biosynthesis. Elucidating the metabolic pathway of tunicamycins and gaining an understanding of the enzymes involved in key bond forming processes would not only be of great academic value in itself, it would also unlock a comprehensive toolbox of biosynthetic machinery for the production of tunicamycin analogues which have the potential to act as novel therapeutic antibiotics or as specific inhibitors of medicinally important NDP-dependent glycosyltransferases. I – Cloning the tunicamycin biosynthetic gene cluster. We report identification of the tunicamycin biosynthetic genes in Streptomyces chartreusis following genome sequencing and a chemically-guided strategy for in silico genome mining that allowed rapid identification and unification of an operon fractured across contigs. Heterologous expression established a likely minimal gene set necessary for antibiotic production, from which a detailed metabolic pathway for tunicamycin biosynthesis is proposed. II – Natural product isolation and degradation. We have developed efficient methods for the isolation of tunicamycins from liquid culture in preparative quantities. A subsequent relay synthesis furnished advanced biosynthetic intermediates for use as precursors in the production of tunicamycin analogues and as substrates for the in vitro characterisation of individual Tun enzymes. III – Functional characterisation of tun gene products. Individual tun gene products were over-expressed and purified from recombinant E. coli hosts, allowing in vitro functional studies to take place. An NMR assay of biosynthetic enzyme TunF showed it acted as a UDP-GlcNAc-4-epimerase. Putative glycosyltransferase TunD showed hydrolytic activity towards substrate UDP-GlcNAc but failed to accept to the expected natural acceptor substrate, providing unexpected insights into the ordering of biosynthetic events in the tunicamycin pathway. Initial studies into the over-expression of the putative sugar N-deacetylase TunE were also described. IV – Towards synthesis of tunicamycin fragments. Investigations into a novel synthesis of D-galactosamine – a structural motif within tunicamycin – led to the unexpected observation of inverted regioselectivity upon RhII-catalysed C-H insertion of a D-mannose-derived sulfamate. This was the first example of N-insertion at the beta- rather than gamma-C-H based on conformation alone and warranted further investigation. The X-ray structure of a key sulfamate precursor offered valuable insights as to the source of this unique selectivity.

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Osazee, Joseph Osamudiamen. "Molecular Docking, Synthesis and Evaluation of Pyrrolo[2,1-c][1,4]benzodiazepines Derivatives as Non-β-lactam β-lactamases Inhibitors." Digital Commons @ East Tennessee State University, 2016. https://dc.etsu.edu/etd/3082.

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Our research aim was to design, synthesize, and study the competitive enzyme inhibition kinetics of pyrrolo[2,1-c][1,4]benzodiazepine (PBD) derivatives as potential non-²-lactam ²-lactamase inhibitors. All compounds (1-13) passed the Lipinski’s rule of 5 test and were docked into the active site of TEM-1 ²-lactamase. PBD derivatives 1-7 were synthesized in high yields and tested for their potency against TEM-1 and P99 ²-lactamases. Kinetic data showed that compounds 1, 4, 5, and 7 possessed inhibitory activity against TEM-1 ranging from 4-34 %. Docking results revealed significant interactive spanning of the active site of TEM-1 by PBDs. The limited inhibitory activity of the compounds, 1-7 could be attributed to the lack of solubility and bulky nature of the molecules, thus limiting the optimal ligand-enzyme interactions. 1,2,4- Oxadiazolinones (8-13) were further synthesized to reduce the steric hindrance of the PBD scaffolds while promoting the electrophilicity of the potentially active lactam and also evaluated for potency.

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Knight, J. "New synthetic methods for the synthesis of #BETA#-lactam antibiotics." Thesis, University of Southampton, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.373921.

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Freskos, John N. "Synthesis and chemistry of 3-cyanophthalides /." The Ohio State University, 1985. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487262825078317.

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21

Archibald, Sarah Catherine. "Approaches towards the synthesis of ebelactone A using organosilicon chemistry." Thesis, University of Cambridge, 1993. https://www.repository.cam.ac.uk/handle/1810/272259.

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O'Riordan, Timothy Jeremiah Cornelius. "Synthesis of the pyrrolidinone core of oxazolomycin A." Thesis, University of Oxford, 2009. http://ora.ox.ac.uk/objects/uuid:298746d3-69df-47b9-8a83-7949df1c94dc.

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This thesis describes the development of synthetic strategies towards the densely functionalised pyrrolidinone core of the polyene β-lactone-γ-lactam antibiotic oxazolomycin A. Chapter 1 The oxazolomycins The oxazolomycins, a unique class of biologically active molecules containing a spiro-fused β-lactone-γ-lactam ring system are introduced. The isolation, structural elucidation and biological properties of the oxazolomycins as well as those of the structurally related inthomycins are reviewed. Chapter 2 Previous syntheses The two total syntheses of neooxazolomycin and the synthetic approaches to the pyrrolidinone core of oxazolomycin A and KSM-2690 B are evaluated. Chapter 3 Project aims An outline of the synthetic strategy employed in this project and details of the novel retrosynthesis of the pyrrolidinone core of oxazolomycin A are discussed. Chapter 4 Synthetic studies towards the pyrrolidinone core of oxazolomycin A The synthetic studies carried out towards the pyrrolidinone core of oxazolomycin A are described in detail. The preparation of an advanced intermediate containing the five chiral centres, four of which are contiguous, was achieved in twenty steps as a single diastereomer and as a single enantiomer. Chapter 5 Synthetic studies towards the middle fragment of oxazolomycin A A novel synthetic approach to the diene fragment contained in oxazolomycin A is reported. The formal synthesis of a dienyl iodide, in four fewer steps than previously reported was accomplished. Chapter 6 Conclusions and future work A summary of the synthetic work reported in this thesis and proposals for future study are presented. Chapter 7 Experimental Full experimental procedures and characterisation of compounds are reported. Chapter 8 References A complete list of citations employed in the previous seven chapters is provided.

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Haddad, Jalal. "Synthesis and chemistry of some quinoline-5,8-diones." Virtual Press, 1994. http://liblink.bsu.edu/uhtbin/catkey/917048.

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The synthesis of several 7-substituted analogs of 2-methylquinoline-5,8-dione and their chemistry are described. In this investigation the following compounds were prepared.5,7-Diformamido-8-hydroxy-2-methylquinoline (207), 7-formamido-2methylquinoline-5,8-dione (199), 7-acetamido-2-methylquinoline-5,8-dione (6), 7-isobutyramido-2-methylquinoline-5,8-dione (200), 7-amino-2-methylquinoline-5,8-dione (210), 7-amino-6-chloro-2-methylquinoline-5,8-dione (213), 7-methoxy-2-methylquinoline5,8-dione (214), 7-ethoxy-2-methylquinoline-5,8-dione (215), 7-isopropyloxy-2methylquinoline-5,8-dione (216), 7-amino-5-ethyl-5-hydroxy-2-methylquinoline-8-one (218), 7-acetamido-5-ethyl-5-hydroxy-2-methylquinoline-8-one (220), and 7-chloro-2methylquinoline-5,8-dione (222).Trimetylacetic formic anhydride (206) was prepared according to McGarvy,s 68 method from treatment of sodium formate (204) and trimethylacetyl chloride (203) in the presence of poly (4-vinylpyridine-N-oxide) (205) as catalyst. 7-Formamido-2methylquinoline-5,8-dione (199) was prepared according to the following general procedure. 8-Hydroxy-2-mehylquinoline (5) was reacted with a 70% mixture of HNO3/H2SO4 to produce 5,7-dinitro-8-hydroxy-2-methylquinoline (18). Compound 18 was reduced by H2/Pd-C in the presence of HCl and then the resulting 5,7-diamino-8-hydroxy-2 methylquinolin-5,8-dione hydrochloride salt (198) reacted with trimethylacetic formic anhydride to produce 5,7-diformamido-8-hydroxy-2-methylquinoline-5,8-dione (207). Compound 207 was treated with a solution of potassium dichromate in acetic acid-water mixture to give product 199.7-Acetamido-2-methylquinoline-5,8-dione (6) was prepared from reaction of a solution of 198 with acetic anhydride in the presence of sodium acetate and sodium sulfite followed by oxidation with potassium dichromate in acetic acid-water solution. 7-Isobutyramido-2methylquinoline-5,8-dione (200) was prepared according to following procedure. Treatment of a solution of 198 with isobutyric anhydride in the presence of sodium acetate and sodium sulfite afforded 5,7-diisobutyramido-8-isobutyroxy-2-methylquinoline (212). Partial hydrolysis of 212 in boiling methanol-water mixture gave 5,7-diisobutyramido-8-hydroxy-2methylquinoline (211). Oxidation of 211 by a solution of potassium dichromate in acetic acid-water mixture afforded product 200.7-amino-2-methylquinoline-5,8-dione (210) was prepared from alcoholysis of 7-acylamino-2-methylquinoline-5,8-diones 6, 199,and 200 with methanol and sulfuric acid. 7-Alkoxy-2-methylquinoline-5,8-diones 214, 215, and 216 were prepared from reaction of 7-acetamido compound 6 with alcohols in the presence of sulfuric acid. Reaction of 7-acylamino compounds 6, 199, and 200 with methanol in the presence of hydrogen chloride gas at 60°C afforded 7-amino-6-chloro-2-methylquinoline-5,8-dione (213).Reaction of compound 210 with diethylaluminum cyanide gave 7-amino-5-ethyl-5hydroxy-2-methylquinoline-8-one (218). The same reaction was carried out on compound 6 to give 7-acetamido-5-ethyl-5-hydroxy-2-methylquinoline-8-one (220).1-[(tert-Butyldimethylsilyl)oxy]-2-methyl-l-aza-1,3-butadiene (4) was prepared from treatment of methyl vinyl ketone (210) and t-butylmethylsilylhydroxylamine (202) in dichloromethane in the presence of molecular sieves. Cycloaddition reaction of a solution of 4 in dichloromethane with 2,6-dichloro-1,4-benzoquinone (221) in sealed tube afforded 7-chloro-2-methylquinoline-5,8-dione (222).
Department of Chemistry

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24

Stansfield, Ian. "Synthetic and modelling studies on macrolide antibiotics : total synthesis of novel analogues of erythromycin A." Thesis, University of Cambridge, 1995. https://www.repository.cam.ac.uk/handle/1810/271994.

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25

Burnside, I. J. "Synthetic studies on macrolide antibiotics : the total synthesis of (+)-(6R)-Fluoro-6-deoxy-(9S)-dihydroerythronolide A." Thesis, University of Cambridge, 1996. https://www.repository.cam.ac.uk/handle/1810/273078.

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26

Deaguero, Andria Lynn. "Improving the enzymatic synthesis of semi-synthetic beta-lactam antibiotics via reaction engineering and data-driven protein engineering." Diss., Georgia Institute of Technology, 2011. http://hdl.handle.net/1853/42727.

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Semi-synthetic β-lactam antibiotics are the most prescribed class of antibiotics in the world. Chemical coupling of a β-lactam moiety with an acyl side chain has dominated the industrial production of semi-synthetic β-lactam antibiotics since their discovery in the early 1960s. Enzymatic coupling of a β-lactam moiety with an acyl side chain can be accomplished in a process that is much more environmentally benign but also results in a much lower yield. The goal of the research presented in this dissertation is to improve the enzymatic synthesis of β-lactam antibiotics via reaction engineering, medium engineering and data-drive protein engineering. Reaction engineering was employed to demonstrate that the hydrolysis of penicillin G to produce the β-lactam nucleus 6-aminopenicillanic acid (6-APA), and the synthesis of ampicillin from 6-APA and (R)-phenylglycine methyl ester ((R)-PGME), can be combined in a cascade conversion. In this work, penicillin G acylase (PGA) was utilized to catalyze the hydrolysis step, and PGA and α-amino ester hydrolase (AEH) were both studied to catalyze the synthesis step. Two different reaction configurations and various relative enzyme loadings were studied. Both configurations present a promising alternative to the current two-pot set-up which requires intermittent isolation of the intermediate, 6-APA. Medium engineering is primarily of interest in β-lactam antibiotic synthesis as a means to suppress the undesired primary and secondary hydrolysis reactions. The synthesis of ampicillin from 6-APA and (R)-PGME in the presence of ethylene glycol was chosen for study after a review of the literature. It was discovered that the transesterification product of (R)-PGME and ethylene glycol, (R)-phenylglycine hydroxyethyl ester, is transiently formed during the synthesis reactions. This never reported side reaction has the ability to positively affect yield by re-directing a portion of the consumption of (R)-PGME to an intermediate that could be used to synthesize ampicillin, rather than to an unusable hydrolysis product. Protein engineering was utilized to alter the selectivity of wild-type PGA with respect to the substituent on the alpha carbon of its substrates. Four residues were identified that had altered selectivity toward the desired product, (R)-ampicillin. Furthermore, the (R)-selective variants improved the yield from pure (R)-PGME up to 2-fold and significantly decreased the amount of secondary hydrolysis present in the reactions. Overall, we have expanded the applicability of PGA and AEH for the synthesis of semi-synthetic β-lactam antibiotics. We have shown the two enzymes can be combined in a novel one-pot cascade, which has the potential to eliminate an isolation step in the current manufacturing process. Furthermore, we have shown that the previously reported ex-situ mixed donor synthesis of ampicillin for PGA can also occur in-situ in the presence of a suitable side chain acyl donor and co-solvent. Finally, we have made significant progress towards obtaining a selective PGA that is capable of synthesizing diastereomerically pure semi-synthetic β-lactam antibiotics from racemic substrates.

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27

Ha, Deok-Chan. "Part I: Synthesis of carbapenems and aminosaccharides ; Part II: Studies toward a synthesis of gelsemine /." The Ohio State University, 1987. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487324944215364.

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28

Schofield, C. "Chemical and enzymatic synthesis of beta-lactam antibiotics." Thesis, University of Oxford, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.355775.

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29

Haley, Patrick John. "Studies towards the biomimetic synthesis of polyether antibiotics." Thesis, University of Cambridge, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.359749.

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30

Hadfield, Peter Stanley. "The synthesis of #gamma#-lactam mimics of #beta#-lactam antibiotics." Thesis, University of Huddersfield, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.338614.

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31

Macdonald, Gregor James. "The synthesis of naturally occuring antibiotics of the manumycin group." Thesis, University of York, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.242164.

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32

Parisi, M. F. "Synthetic and biosynthetic studies on antibiotics." Thesis, University of Oxford, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.371556.

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33

Reza, Khalid. "Synthetic approaches to the benzanthraquinone antibiotics." Thesis, University of Salford, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.258376.

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34

Wang, Sho-nong. "Contributions to the synthesis of higher hetero-oligosaccharides and anisomycin antibiotics." Thesis, University of Ottawa (Canada), 1996. http://hdl.handle.net/10393/10272.

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Section 1. Improvements were made in the procedures for the preparation of hexa-O-acetyllactal and of the lactosamine donors 3,6-di-O-acetyl-4-O-(2,3,4,6-tetra-O-acetyl-$ \beta$-D-galactopyranosyl)-2-deoxy-2-phthalimido-$ \beta$-D-glucopyranostl chloride, bromide, and trichloroacetimidate. In particular, introduction of halogen by means of dichloromethyl methyl ether and trimethylsilyl bromide was found to be superior to previous methods. The new disaccharide methyl 2-benzamido-4,6-O-benzylidene-2-deoxy-3-O-(2,3,4,6-tetra-O-acetyl-$ \beta$-D-galactopyranosyl)-$\alpha$-D-glucopyranoside was synthesized by the Koenigs-Knorr method and was converted, in a one-pot acetolysis reaction, into phenyl-(1,2-dideoxy-4,6-di-O-acetyl-3-O-(2,3,4,6-tetra-O-acetyl-$\beta$-D-galactopyranosyl)-$ \alpha$-D-glucopyrano) (2$\sp\prime,1\sp \prime$:4,5) -2-oxazolinium acetate, a new donor of the lacto-N-biosyl unit in glycosylations. Furthermore, it was discovered that trimethylsilyl triflate-promoted transfer of a 3-O-benzylated D-galactose 1-acetate to OH-3 of a partially blocked methyl N-benzoylglucosaminide led not only to formation of the expected disaccharide linkage but at the same time converted the acceptor glycoside into an oxazoline, thus producing a new lacto-N-biose donor having a temporarily blocked 3$\sp\prime$-position, which should be useful for the design of block syntheses of higher heterosaccharides. Peracetylated 2-azido-2-deoxylactose and the corresponding 1,3,6,2$\sp\prime,6\sp\prime$-pentaacetate (a new lactosamine acceptor equivalent) were synthesized from hexaacetyllactal by the azidonitration method, and a number of other lactosamine and lactose acceptors having unprotected OH-3$\sp\prime$ and OH-4$\sp\prime$ groups were prepared by established procedures. Methyl 4,6-di-O-acetyl-2-benzamido-2-deoxy-3-O-(2,4,6-tri-O-benzoyl-3-O-benzyl-$\beta$-D-galactopyranosyl)-$ \alpha$-D-glucopyranoside was synthesized, to be used as a lacto-N-biose acceptor after deprotection of O-3$\sp\prime.$ Three similarly substituted methyl glycosides of 3-$\beta$-D-galactopyranosyl-D-glucose ("isolactose") were prepared by condensations of various D-galactopyranosyl bromides with methyl 2-O-benzoyl-4,6-O-benzylidene-$ \alpha$-D-glucopyranoside in order to obtain molecules that may serve as "isolactose" acceptors after deprotection at O-3$\sp\prime.$ Observations concerning the stability of benzyl ethers in these reactions were recorded. Treatment of 1,3,4,6-tetra-O-acetyl-2-deoxy-2-phthalimido-$\beta$-D-glucopyranose with tributyltin benzyloxide in the presence of stannic chloride did not lead to the expected benzyl glycoside but gave in high yield a new disaccharidic coupling product, i.e., 2,2$\sp\prime$-dideoxy-2,2$\sp\prime$-diphthalimido-$ \beta,\beta$-trehalose hexaacetate, and a minor product which is possibly its $\alpha,\beta$-anomer. Section 2. 1-Amino-1-deoxy-D-xylitol hydrochloride was sequentially N-carbobenzyloxylated and isopropylidenated. The 1-benzyloxycarbonylamido-1-deoxy-2,3:4,5-di-O-isopropylidene-D-xylitol so obtained was subjected to partial hydrolysis for removal of the 4,5-acetonide, followed by periodate glycol cleavage to give 4-benzyloxycarbonylamido-2,3-O-isopropylidene-L-erythrose. This aldehydo sugar was reacted with p-methoxyphenylnitromethane to furnish 5-benzyloxycarbonylamido-3,4-O-isopropylidene-1-(4-methox yphenyl)-1-nitropentane-2,3,4-triol. Its 2-acetate was subjected to dehydroacetoxylation, giving the corresponding nitroalkene, 5-benzyloxycarbonylamido-3,4-O-isopropylidene-1-(4-methoxyphenyl)-1-nitro-1-pentene-3,4-diol. Deacetonation then gave the corresponding free diol. Attempts to effect cyclizing Michael addition in these nitroalkenes, to construct the 2-(p-methoxybenzyl)-substituted pyrrolidine-3,4-diol structure of anisomycin have so far been unsuccessful.

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35

Daher, Samer Sami. "SYNTHESIS AND EVALUATION OF ANTIBIOTICS TARGETING RESISTANT PATHOGENS AND EFFORTS TOWARD LONGIFOLENE." Diss., Temple University Libraries, 2019. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/578112.

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Chemistry
Ph.D.
Various organizations, including the Centers for Disease Control and Prevention (CDC), and World Health Organization (WHO) have declared infections caused by multi-drug resistance pathogens as an “emergent global disease” and a “major public health problem.” The reports were issued in response to two seismic developments in 2016. The first report of antibiotic-resistant bacteria addresses the story of the American patient carrying the mcr-1 gene, which confers resistance to the antibiotic colistin, while the second report proclaims the pathetic death of U.S. patient from septic shock attributed to bacterial infection resistant to treatment with 26 antibiotics. Thus, the rapid development of bacterial resistance to antibiotics coupled with marked changes in the pharmaceutical sector has resulted in a global health crisis; so new antibiotics are urgently needed. Approximately two-thirds of all antibiotics are derived from natural products, so the structural modification of natural products-derived antibiotics by either semi- or total synthesis is a highly successful strategy for discovering novel drugs to address bacterial resistance. My Ph.D. research project comprises of analog development for three main classes: macrolides, albocycline, and aminoglycosides. Macrolides in general and ketolides, in particular, have been widely successful in treating various serious infections affecting lungs (e.g., pneumonia) and skin (e.g. cellulitis) over the past decades. My research of macrolides orients towards establishing a structure-activity relationship (SAR) via developing analogs of solithromycin (current-leading ketolide), that can be accessed via Cu (I) combinatorial click chemistry inspired by Sharpless, in which a library of synthesized and commercial alkynes have been clicked at N-11 azide side chain. Alternatively, synthetic approaches have been applied on the macrolide azide, in order to establish novel scaffolds termed as bis-clicked products that possess supplementary binding pockets. Despite the fact that albocycline (macrolactone) shares similar structural scaffolds with macrolides, it still possesses promising activity for treating methicillin-resistant Staphylococcus (MRSA) as well as vancomycin-resistant strains (MIC = 0.5−1.0 μg/mL). My research of albocycline has established a library of albocycline analogs accessed via cultured albocycline that is isolated from Streptomyces maizeus. However, attempts to functionalize various sites of the albocycline core resulted in poor biological activity reflected with high minimum inhibitory concentrations (MICs). Therefore, developing novel analogs with improved properties required a better understanding of the mode of action. Initial reports indicated the possibility of albocycline inhibiting the bacterial cell wall synthesis, particularly the peptidoglycan that involves various downstream enzymes MurA to MurZ. Using biochemical pathways and molecular modeling, we concluded that albocycline has an alternative bacterial target. Current efforts in collaboration with Paul Dunman at The University of Rochester (School of Medicine), initiated a genetic approach to identify the target. In this regard, four albocycline-resistant S. aureus strains have been identified by whole-genome sequencing of both mutant and parent (wild-type) and studied to identify the target of albocycline. Preliminary data suggest that albocycline exerts a direct inhibition to the nicotinate pathway in Bacillus subtilis cells, which indirectly causes the blockage of peptidoglycan biosynthesis. In short, the long-term goal revolves toward delivering new antibiotics to avert a post-antibiotic era after gaining a better understanding of the antibacterial mechanism of action. Typical strategies to antibiotic discovery require chemical synthesis, lead optimization, accompanied by tedious compound characterization followed by biological evaluation. These approaches are time-consuming and expensive in terms of labor, cost of reagents, and solvents. A promising solution to this problem is found in the emerging field of target-guided synthesis (TGS), wherein the bacterial target assembles its own inhibitor following the principles of fragment-based drug design leading to acceleration in the drug discovery process. On this subject, we have developed seven novel analogs of aminoglycoside neomycin via Cu (I) click chemistry and tested their MICs against resistant strain pikR2. MIC results revealed few analogs that share similar potency with neomycin against pikR2, illustrating the potential for expanding this method further with in situ click experiments. The viability of the proposed in situ click is predicted on previous work established by the Andrade lab, which could explore novel analogs addressing resistance concerns. My final research project centers on the recent advances of C–H activation and its tremendous growth as a hot topic in the synthetic field through the application of longifolene. This triggers us to take advantage of 1,5-Hydrogen Atom Transfer (HAT) to afford cyclization of the seven-membered ring of the molecule. Although longifolene has been previously accessed, it presents a challenging synthesis due to the intricate carbon-carbon framework. Innovative methodology relying on a modified Suarez oxidation (oxygen-centered radical) is proposed to accomplish a formal synthesis of longifolene, which can be expanded for much broader applications.
Temple University--Theses

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36

Cox, G. "Synthesis of carbocyclic analogues of the #beta#-lactam antibiotics." Thesis, University of Huddersfield, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.374894.

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37

Zhang, Jianjun. "Library Synthesis of Anticancer and Antibacterial Agents via Azide Chemistry." DigitalCommons@USU, 2010. https://digitalcommons.usu.edu/etd/711.

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Various anticancer and antibacterial agents have been synthesized via azide chemistry by taking advantage of carbohydrate. Starting from the synthesis of 14 glycosyl azides, a library of carbohydrate-oxazolidinone conjugates and a library of carbohydrate-cyclopamine conjugates with biological interests were synthesized based on a highly efficient "click reaction" assisted by sonication. Some of the conjugates have improved solubility and enhanced anticancer activity. A library of neomycin B derivatives with various modifications at the 5" position has been synthesized. Two leads exhibit prominent activity against both methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). Antibacterial activities were measured when combined with other clinically used antibiotics and significant synergistic activities were observed. Three different classes of aryl N-glycosides have been synthesized by employing 1,4-naphthoquinone and glycosyl azides undergoing a [2+3] cycloaddition. Alkyl azides can also undergo the same cycloaddition. After the removal of the protecting group, a library of 9,10-anthraquinone derivatives with potential anticancer activity and a library of 2-aminomethylene-1,3-indanediones with novel antibacterial activity have been developed, respectively. A one-pot three-component [2+3] cycloaddition for the synthesis of 1-alkyl 1H-naphtho[2,3-d][1,2,3]triazole-4,9-dione and 2-alkyl 2H-naphtho[2,3-d][1,2,3] triazole-4,9-dione has been developed. By taking the advantage of their difference in basicity, both products can be obtained in good purity. Using an allylic azide rearrangement, a convenient method has been developed for the synthesis of several 2',3'-dideoxyaminoglycosides. The antibacterial activity of these novel aminoglycosides also confirms the indispensable role of the 2'-NH2 group for both neomycin and kanamycin classes of aminoglycosides. A novel structural motif containing the hexylaminocarbonyl groups at O-5 and/or O-6 of 2',3'-dideoxyneamine could lead to the production of new aminoglycosides against resistant bacteria.

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38

Robinson, Louise. "The development of short synthetic routes to polyoxomacrolide antibiotics." Thesis, University of Bristol, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.317848.

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39

Wiedeman, Paul Edward. "A relay approach toward the synthesis of (+)-pleuromutilin /." The Ohio State University, 1985. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487261553056632.

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40

Wright, Peter Maughan. "Multiplicative Expansion of the Pool of Fully Synthetic Tetracycline Antibiotics." Thesis, Harvard University, 2012. http://dissertations.umi.com/gsas.harvard:10504.

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This thesis describes the development of chemical pathways for the preparation of more than 80 novel fully synthetic tetracyclines with structural variability at positions C5 and C5a. Progress toward the synthesis of 5-hetero-tetracyclines, another new class of tetracycline antibiotics, is also described. The results detailed herein – including successful C-ring-forming Michael–Claisen cyclizations of numerous modified AB precursors with just a few of the extraordinarily diverse D-ring precursors known to be effective nucleophiles in this key coupling reaction – represent the first steps toward a multiplicative expansion of the pool of fully synthetic tetracyclines. Novel and versatile $\beta$-functionalization reaction sequences employing tris(methylthio)methyllithium and 2-lithio-1,3-dithiane have been developed to transform the AB enone 10 (the key precursor to fully synthetic tetracyclines) into a diverse range of $\beta$-substituted AB enone products, including a highly efficient, single-operation method for the synthesis of a $\beta$-methyl ester-substituted AB enone (20). It is demonstrated that the six-membered C ring of tetracyclines comprising a C5a quaternary carbon center (e.g. 29) can be assembled by stereocontrolled coupling reactions of $\beta$-substituted AB enones and o-toluate ester anion D-ring precursors. A C5a–C11a-bridged cyclopropane tetracycline precursor (37) was found to undergo efficient and regioselective ring-opening reactions with a range of nucleophiles in the presence of magnesium bromide, thus providing another avenue for the preparation of fully synthetic tetracyclines containing an all-carbon quaternary center at position C5a. The AB enone 10 has also been transformed into structurally diverse $\gamma$-substituted AB precursors, which in turn have been converted into fully synthetic tetracyclines with unprecedented modifications at position C5, including 5-fluorotetracyclines such as 94. Numerous fully synthetic tetracyclines and tetracycline precursors have been shown to serve as diversifiable branch-points, allowing maximally expedient synthesis of C5- and C5a-substituted tetracyclines by late-stage diversification. The substrate scope of the Michael–Claisen cyclization reaction has been expanded to include new heterocyclic enone electrophiles such as dihydro-4-pyridones, affording cycloadducts such as 142. In this way, the viability of an iterative Michael–Claisen strategy for constructing 5-hetero-tetracyclines has been established. Numerous examples in this thesis serve to further demonstrate the broad applicability of the Michael–Claisen cyclization reaction as a powerful method for the assembly of stereochemically complex six-membered rings.
Chemistry and Chemical Biology

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41

Ramcharitar, Steve Harrinarine. "The synthesis of macrocyclic ketones and lactones : approaches to naturally occurring macrolyde antibiotics." Thesis, University of Oxford, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.302875.

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42

Baker, Simon. "Studies towards the total synthesis of BU-4794F and alkene metathesis in the synthesis of novel Î²-lactam antibiotics." Thesis, Imperial College London, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.326162.

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43

Li, Shuoliang, and 李碩梁. "Application of the Nazarov cyclization reaction to the synthesis of guanacastepenes and taiwaniaquinoids." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2006. http://hub.hku.hk/bib/B38348974.

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44

Sussman, Robin Judith. "I. Synthesis of C4-Modified Tetracyclines II. Aldolizations of Pseudoephenamine Glycinamide and Applications Toward the Synthesis of Monocyclic β-Lactam Antibiotics." Thesis, Harvard University, 2015. http://nrs.harvard.edu/urn-3:HUL.InstRepos:17467383.

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Part one of this thesis describes the production of C4-modified tetracycline derivatives. Our synthetic strategy originally targeted SF2575, a C4-oxygenated tetracycline analog with antiproliferative properties, but was later amended to target antibacterial C4-oxygentaed minocycline analogs. The C4-modified tetracyclines were accessed utilizing a strategy based on the Myers’ platform to 6-deoxytetracyclines (Michael–Claisen cyclization between AB enone 71 and D-ring phenyl esters 44 or 84) in addition to the 4th generation route to tetracycline key AB enone (Michael–Claisen cyclization between B-ring enone 8 and isoxazole 21). The crucial enabling step along this route was the C4-epimerization of Boc bis-carbonate 82 to Boc bis-carbonate 83. Five C4-modified tetracyclines were synthesized and their antibiotic properties were assessed. Part two of this thesis describes the development of a new chiral glycine equivalent for aldol reactions, pseudoephenamine glycinamide ((R,R)-179), and an application of this methodology toward the production of C4-disubstituted monocyclic β-lactam antibiotics. Asymmetric aldolization of pseudoephenamine glycinamide with aldehydes and ketones produces syn-β-hydroxy-α-amino amides 180 with high diastereoselectivities and without the use of protecting groups. These aldol adducts can be transformed into enantiomerically enriched alcohols, ketones, and carboxylates, many of which enable powerfully simplified syntheses of various antibiotics. Utilization of the newly developed methodology enabled access to β,β’-disubstituted-β-hydroxy-α-amino acids. Elaboration of these substrates provided novel C4-disubstitued monobactam analogs, an underrepresented class of β-lactam antibiotics. Four C4-disubstituted monocyclic β-lactam antibiotic candidates were synthesized and their antibiotic activities were assessed.
Chemistry and Chemical Biology

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45

Mandhapati, Appi Reddy. "Synthesis of apramycin and paromomycin derivatives as potential next generation aminoglycoside antibiotics and chemistry of isothiocyanato sialyl donors." Thesis, Wayne State University, 2016. http://pqdtopen.proquest.com/#viewpdf?dispub=10153408.

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AGAs are clinically important antibacterials for human therapy and have long been used as highly potent antibiotics for treating several bacterial infections. The fidelity of protein synthesis is affected by AGAs in the course of binding to specific sites of the bacterial rRNA. The clinical use of AGAs and their applications as therapeutics is restricted by toxicity (irreversible ototoxicity and reversible nephrotoxicity) and by the resistance of pathogens. The objective of this research was the development of proficient AGAs that are less toxic (i.e., more selective) and that evade resistance. The first three chapters of this thesis are aimed towards developing new aminoglycoside antibiotics with the emphasis on their chemical synthesis, and the biological evaluation of newly synthesized analogues, as well as the exploration of structure-activity relationships to understand the mechanism of their antimicrobial activity. In particular, studies have focused on the modification of the aminoglycosides apramycin and paromomycin so as to develop the next generation of potent AGAs.

Chapter two reveals the importance of the 6' and N7' positions of the apramycin by investigation of the antibacterial activity and antiribosomal activity of the ten apramycin derivatives which were synthesized by modifying these locations. The effect of such modifications on antiribosomal activity is discussed in terms of their influence on drug binding to specific residues in the decoding A site. This information is useful in the development of a structure activity relationship for the antibacterial activity of the apramycin class of aminoglycosides and will also assist in the future design and development of more active and less toxic aminoglycoside antibiotics.

Chapter three describes the structure-based design of an improved paromomycin derivative which carries an apramycin-like bicyclic ring I and a conformationally restricted hydroxyl or amine functionality. The influence of the bicyclic paromomycin 6'-hydroxy or amine groups on the binding pattern between AGA and bacterial RNA was investigated by using cell free translational assays. It was found that the bicyclic paromomycin derivative 155 with the equatorial 6’-hydroxy group has a better activity profile than parent paromomycin.

In chapter four, an efficient sialyl donor was developed for the challenging α-sialylation by means of a highly electron withdrawing isothiocyanato group incorporated at C-5 position sialic acid. The isothiocyanato sialyl donor 218 proved to be an excellent α-directing group in sialylation for a wide range of acceptors, and provided high yields. Further, the sialylation of corresponding sialyl phosphate donor 231 was also demonstrated to give excellent selectivity, but yields are lower due to competing elimination. In addition, the rich chemistry of isothiocyanate functionality is explored to introduce a variety of novel functionalities at the 5-position of the sialosides including deamination, an alkyl chain, various amides, and guanidine derivatives.

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46

Basu, Shubhamita. "STUDIES TOWARDS THE TOTAL SYNTHESIS OF VANCOMYCIN AGLYCON." Case Western Reserve University School of Graduate Studies / OhioLINK, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=case1183157258.

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47

Swallow, Isabella Diane. "Probes for bacterial ion channels." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:d42d13dd-dd0c-451b-bd00-e06f84350335.

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Abstract:

Using three complementary approaches, this work sought to tackle the widespread problem of antibiotic resistance. To circumvent the resistance mechanisms developed by bacteria, it is necessary to establish drug candidates that act on novel therapeutic targets, such as the ion channels used by bacteria to modulate homeostasis. Examples include the potassium efflux channel, Kef, and the mechanosensitive channel of small conductance, MscS, which are not found in humans. How these targets function must be well understood before drug candidates can be developed, as such, their identification and investigation is often accompanied by the evolution of the analytical techniques used to study them. Membrane protein mass spectrometry is one technique showing potential in the study of ion channels. However, spectra can be clouded by the detergents used to solubilise ion channels from their native membranes. Undertaken herein was the synthesis of some fluorescent glycolipid detergents, which it was hypothesised could be encouraged to dissociate from ion channels via laser-induced excitation within the gas phase of a mass spectrometer, thereby improving the clarity with which spectra can be obtained. For Kef, an unconfirmed mechanism of action had previously been proposed. To explore the suggestion that sterically-demanding central residues are important for channel activation, solid phase peptide synthesis was used to isolate three tripeptide analogues of N-ethylsuccinimido glutathione, a known activator with a high affinity for Kef. A competition fluorescence assay suggested these tripeptides bound to Kef with an affinity lower than predicted, allowing the conclusion that a more detailed assessment of the steric bulk required for activation was necessary before a mechanism of action could be confirmed. Lysophosphatidylcholine has been shown to activate MscS, although it is not known how. Affinity chromatography between MscS and lysophosphatidylcholine was proposed as a means by which specific binding interactions could be investigated. For this technique an amino-derivative of lysophosphatidylcholine was necessary and its challenging synthesis is also detailed herein.

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Yatchang, Marina Fosso. "Synthesis and Biological Activity of Aminoglycosides and 1,4-Naphthoquinone Derivatives." DigitalCommons@USU, 2012. https://digitalcommons.usu.edu/etd/1371.

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The research described in this dissertation is at the interface of organic chemistry and biology, and it aimed at designing and synthesizing biologically active molecules for the possible development of therapeutic agents. Spinal muscular atrophy is an incurable disease that affects 1 in every 6000 babies, making it the leading genetic cause of infant mortality. While no treatment is available, efforts are being taken to solve this issue. Part of the work outlined in this dissertation was carried out in collaboration with researchers from the University of Missouri to investigate a potential therapeutic for this disease. In addition, the continuous outbreak of diseases caused by bacteria demands for new and improved antibiotics that could help eradicate those pathogens. My research thus allowed me to discover molecules with interesting activity against bacteria for the possible development of potential antibacterial agents. Finally, my research also allowed me to develop potential agro fungicides, which are still very much needed nowadays. Many crop diseases are due to fungal infections,which globally cause enormous economic losses. The use of fungicides is still the main strategy to control these diseases. However, current agro fungicides show some limitations. This is illustrated with Fusarium head blight (FHB), a destructive and costly disease of wheat, barley and other small grains, whose economic losses in the Central United States alone were estimated to $2.7 billion.

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Sagnou, Marina J. "Rational design, synthesis and biological evaluation of prodrugs of the pyrrolobenzodiazepine family of antitumour antibiotics." Thesis, University of Portsmouth, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.368470.

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Tiwari, Rohit. "COMPUTATIONAL AND SYNTHETIC STUDIES ON ANTIMETABOLITES FOR ANTICANCER-, ANTIVIRAL-,AND ANTIBIOTIC DRUG DISCOVERY." The Ohio State University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=osu1267819591.

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Dissertations / Theses on the topic 'Antibiotic synthesis/chemistry'

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