Synthesis Of Bioactive Heterocycles, Shaila Akter Shetu

Theses and Dissertations

The Discovery of a variety of heterocyclic drugs for the treatment of cancer and other diseases (e.g, neglected tropical diseases) is a medical breakthrough and inspiring for the research community as a whole. A wide range of natural, semi-synthetic, and synthetic anticancer drugs are synthesized using various methods. Among them, β -lactams stand out as a novel class of antibiotics that has different types of biological as well as anti-cancer properties. β -lactam has become a premier and active research subject towards the development of revolutionary anti-cancer drugs. In recent years, a large amount of investigations have been done to …

Extraction And Partial Purification Of An Antibiotic-Like Compound From The Soil Bacterium Rhodococcus Strain Kchxc3, Elizabeth Bond

Undergraduate Honors Theses

Rhodococcus bacteria have many secondary metabolic pathways that may produce novel natural products. The bacterium Rhodococcus strain KCHXC3 was isolated from a soil sample collected near Kingsport, Tennessee and was found to produce an inhibitory compound active against a broad array of bacterial species, including the Gram negative pathogen Shigella sonnei. The aim of this research is to extract and purify the compound for future structure elucidation. A mixture of compounds from 3 month old agar plates inoculated with strain KCHXC3 was extracted using ethyl acetate. The crude extract was then partially purified utilizing a Sephadex LH-20 column, followed …

Antibacterial Activity, Structure-Activity Relationships, And Scale-Up Reaction Of 1,3,4-Oxadiazoles, Olivia Marie Smith

Undergraduate Honors Thesis Projects

Oxadiazoles are compounds in the field of organic chemistry that have been gathering interest in the medicinal chemistry and microbiology communities for their biological properties, which range from anti-inflammatory agents, to chemotherapy drugs, to antibiotics. The synthesis of oxadiazoles can be difficult due to the expensive and complex nature of the techniques used as well as the volatile reagents and elevated temperatures that are often required in organic synthesis. The Grote lab has recently developed a new method for the synthesis of 1,3,4-oxadiazoles under mild conditions. The goals of this thesis were thus twofold: to develop a viable scale-up procedure …

Development Of Small Molecule Inhibitors Of Therapeutic Target Enzymes: Paths To Discover Novel Antimicrobials, Thahani Shifna Habeeb Mohammad

Dissertations

The rising antimicrobial resistance to antibiotics is a major global problem, which has been exacerbated by the inappropriate use of antibiotics. The effectiveness of frequently prescribed penicillin derivatives and β-lactamase inhibitors are compromised by the evolution of bacterial β-lactamases and antibiotic-resistant bacteria. Consequently, design and synthesis of small-molecule inhibitors of identified novel antibiotic targets is an urgent unmet medical need. We previously demonstrated that N-functionalized α-aminocyclobutanones can act as peptidomimetic enzyme inhibitors, including inhibition of a key esterase in Francisella Tularensis. The carbonyl of a cyclobutanone is electrophilic due to ring strain, therefore cyclobutanone derivatives can serve as transition state …

Influence Of Conformational Restriction On The Antibacterial Activity And Ribosomal Selectivity Of Aminoglycoside Antibiotics, Michael Gabriel Pirrone

Wayne State University Dissertations

The ever-increasing threat posed by multidrug-resistant infectious bacteria necessitates

the development of novel antibiotics. Aminoglycoside antibiotics are growing in interest due to

their broad spectrum of activity, lack of known drug related allergies, low manufacturing cost,

and their well-studied mechanism of action. The simplification of rational drug design due to the

well-studied mechanism of action is the key to overcoming the issues presented by these drugs,

namely ototoxicity and nephrotoxicity.

A study of the effect of the conformation of the aminoglycoside ring I side chain is

described wherein it was discovered that an increase in a particular conformation augments the …

Antifungal Defense Molecules From Bacterial Symbionts Of North American Trachymyrmex Ants, Georgia Scherer

CMC Senior Theses

Defensive symbioses, in which microbes provide molecular defenses for an animal host, hold great potential as untapped sources of therapeutically useful antibiotics. Fungus-growing ants use antifungal defenses from bacterial symbionts to suppress pathogenic fungi in their nests. Preliminary chemical investigations of symbiotic bacteria from this large family of ants have uncovered novel antifungal molecules with therapeutic potential, such as dentigerumycin and selvamicin.

In this study, the bacterial symbionts of North American Trachymyrmex fungus-growing ants are investigated for antifungal molecules. Plate-based bioassays using ecologically-relevant fungal pathogens confirmed that these bacteria have antifungal activity. In order to purify and identify the antifungal …

Synthesis Of An Ideal Inhibitor For The Lpxc Enzyme, Taejun Lee

Honors Theses

Due to the growing need of antibiotics in modern day medicine, this study attempts to apply a method of medicinal chemistry that would create a novel inhibitor for a lesser known target of gram negative bacteria, the LpxC enzyme. This study proposes that a synthetic plan which consists of combining components of different molecules would create a more effective inhibitor. These components include a binding group for the active site of the enzyme, a hydrophobic chain which has been shown to interact with an allosteric site on the LpxC enzyme, and the isoxazoline ring which interacts with the zinc ion. …

Kinetic Characterization Of Listeria Monocytogenes 2-C- Methyl-D-Erythritol 4-Phosphate Cytidylyltransferase ( Cms ) Enzymes Using High Performance Liquid Chromatography ( Hplc ), Mark Oblazny

Theses and Dissertations

Infectious diseases, with increasing prevalence of antibiotic resistant bacteria, coupled with the declining rate in discovery of antimicrobial agents, impose one of the most significant threats to human health. Here we identify 2-C-methyl-D-erythritol 4-phosphate cytidylyltransferase (CMS) as a valid target for antibiotic development which is an enzyme in pathogenic organisms that leads to the biosynthesis of isoprene precursor molecules. Isoprene molecules are one of nature’s most common building blocks that are vital to many biological metabolic processes and are synthesized via the mevalonic acid dependent (MVA), or methylerythritol phosphate (MEP) pathway. Vertebrates utilize the MVA pathway, while many pathogenic bacteria …

Part 1: Design, Synthesis, And Evaluation Of Novel Gram-Positive Antibiotics Part 2: Synthesis Of Dihydrobenzofurans Via A New Transition Metal Catalyzed Reaction Part 3: Design, Synthesis, And Evaluation Of Bz/Gabaa Α6 Positive Allosteric Modulators, Christopher Michael Witzigmann

Theses and Dissertations

Part 1. Lead compound SK-03-92 represents a new scaffold for antibiotic drug discovery. Development of a new process for the synthesis of analogs has led to the development of a number of new ligands with even more potent activity against gram-positive bacteria, including drug-resistant strains of S. aureus. Compounds 36 and 38 represent some of the most potent analogs developed thus far, and preliminary results indicate that they are also not cytotoxic. Research into a Heck-mediated transition metal catalyzed pathway towards electron-rich stilbenoid analogs has greatly expanded the scope of future SAR studies. This development has led to 14 new …

Development Of In Vivo Systems For Detecting And Studying Ribosome Inhibition By Small Molecules, Shijie Huang

Chemistry and Chemical Biology ETDs

The ribosome is the quintessential antibacterial drug target, with many structurally and mechanistically distinct classes of antibacterial agents acting by inhibiting ribosome function. Detecting and quantifying ribosome inhibition by small molecules and investigating their binding modes and mechanisms of action are critical to antibacterial drug discovery and development efforts. To develop a ribosome inhibition assay that is operationally simple, yet provides direct information on the drug target and the mechanism of action, we have developed engineered E. coli strains harboring an orthogonal ribosome controlled green fluorescent protein reporter that produce fluorescent signal when the O-ribosome is inhibited. As a proof …

Synthesis, Structure-Activity Relationship Study, And Mode Of Action Study Of 1,4-Naphthoquinone Based Anticancer And Antimicrobial Agents, Jaya P. Shrestha

All Graduate Theses and Dissertations, Spring 1920 to Summer 2023

The first three projects involve the synthesis and the mode of action study of 1,4-naphthoquinone based anticancer agents. These anticancer agents are highly potent against a wide range of cancer cell lines. These compounds showed ~8-fold selectivity towards the lung cancer cell line than the normal cell line. We also studied the mode of action and observed that generation of reactive oxygen species is the primary mode of action.

The final project involves the synthesis of multi-cationic antimicrobial agents. These compounds are active against both bacteria and fungi. These compounds are very easy to synthesize and can be scaled up …

Synthesis Of Apramycin And Paromomycin Derivatives As Potential Next Generation Aminoglycoside Antibiotics And Chemistry Of Isothiocyanato Sialyl Donors, Appi Reddy Mandhapati

Wayne State University Dissertations

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 …

Adsorption Of Antibiotics By Vermiculite, Mosa J. Ferdous

Dissertations and Theses

The occurrence of residual antibiotics in the environment has been a worldwide issue and warrants the development of inexpensive yet effective methods for antibiotics removal from contaminated water. In this thesis work, the adsorption of four antibiotics, namely chlorotetracycline (CTC), oxytetracycline (OTC), ofloxacin (OFL), and enrofloxacin (ENR), onto natural vermiculite has been studied using batch (static) and column (dynamic) adsorption techniques. The Langmuir and Freundlich isotherm models were initially used to explain the adsorption processes. The separation factor (RL) values derived from the Langmuir model and the 1/n values derived from Freundlich model in the present investigation were less than …

Synthesis, Rna Binding And Antibacterial Studies Of 2-Dos Mimetics And Development Of Polymer Supported Nanoparticle Catalysts For Nitroarene And Azide Reduction, Venkata Reddy Udumula

Theses and Dissertations

Project I 2-Deoxystreptamine (2-DOS), the most conserved central scaffold of aminoglycosides, is known to specifically recognize the 5'-GU-'3 sequence step through highly conserved hydrogen bonds and electrostatic interactions within and without the context of aminoglycosides (Figure 1a). We proposed that a novel monomeric unnatural amino acid building block using 2-DOS as a template would allow us to develop RNA binding molecules with higher affinity and selectivity than those currently available. Conjugating two or more of the monomeric building blocks by an amide bond would introduce extra hydrogen bonding donors and acceptors that are absent in natural aminoglycosides and increase specificity …

Synthesis Of 4'-O-Glycopyranosyl Paromomycin Aminoglycoside Antibiotics: Influence Of The Glycoside On Antiribosomal, Antibacterial Activity And Utilization Of Electrospray Ionization Mass Spectrometry To Evaluate Reactivity Of Glycosyl Phosphate, Weiwei Chen

Wayne State University Theses

The data in this thesis is trying to address two problems. The first problem is paromomycin associated ototoxicity; the second problem is the lack of precise reactivity data of glycosyl donors in one-pot synthesis.

Paromomycin is out of the market as an antibiotic due to its ototoxicity. Previous work done by Vasella and Böttger's groups identified 4'-O position of paromomycin as a promising site of modification to reduce the side effect. A series of 4'-O-glycopyranosyl paromomycin has been synthesized and tested for their biological activity and selectivity. From the results of anti bacterial ribosomal activity, anti hybrid ribosomal activity and …

Chemoenzymatic Synthesis Of An Analogue Of The Potent Antifungal Mycosubtilin, Mayank Srivastava

Master's Theses and Doctoral Dissertations

Mycosubtilin is a naturally occurring antifungal obtained from Bacillus subtilis that also displays limited antibiotic activity. Structurally, mycosubtilin is a macrocycliclipoheptapeptide of sequence Asn-Tyr-Asn-Gln-Pro-Ser-Asn, with the N-terminal Asn joined by a β-amino fatty acid. Besides the antifungal and antibiotic activities,these molecules are also hemolytic in nature. Hence, the purpose of this study is to synthesize a potent antifungal analogue of mycosubtilin, with a modified β-amino fatty acid, devoid of any hemolytic activity. A chemoenzymatic approach was used to synthesize the cyclic peptide, which involved the synthesis of the linear peptide chain of desired amino acid sequence, thiophenylderivatization of the peptide …

Anti-Germinants As A New Strategy To Prevent Clostridium Difficile Infections, Amber Janece Howerton

UNLV Theses, Dissertations, Professional Papers, and Capstones

Clostridium difficileinfections (CDI) have emerged as a leading cause of hospital-associated complications. CDI is the major cause of antibiotic-related cases of diarrhea and nearly all cases of pseudomembranous colitis. The infective form of C. difficileis the spore, a dormant and hardy structure that forms under stress. Germination of C. difficile spores into toxin producing bacteria in the GI tract of susceptible patients is the first step in CDI establishment. Patient susceptibility occurs with a disruption of the natural gut microbiota by broad-spectrum antibiotics. Antibiotic treatments usually resolve CDI but refractory cases are on the rise. Of great concern is the …

Synthesis And Purification Of Potential Antimicrobial Peptides, Christopher Ryan Snyder

Master's Theses and Doctoral Dissertations

No abstract provided.

Library Synthesis Of Anticancer And Antibacterial Agents Via Azide Chemistry, Jianjun Zhang

All Graduate Theses and Dissertations, Spring 1920 to Summer 2023

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 …

Synthesis Of Carbon Nucleosides : Potential Antibiotics, Jeffery Davis

Senior Scholar Papers

Abstract This paper deals with two synthetic routes designed to yield carbon nucleosides. The C-nucleosides are compounds of potential antibiotic utility. The first approach, designed to yield 4-(2'-deoxyribofuranosyl )-1 ,2,3-triazole (1), consisted of silylation of methyl vinyl ketone (4) to give 2-trimethylsilylosy-l,3-butadiene (6), followed by a crossed aldol condensation with a heteroaromatic aldehyde to yield the aldol l. Epoxidation and cyclization of l was expected to yield the target molecule ~. The initial step, silylation of methyl vinyl ketone (4), was successful. Using model compounds the second step of the synthesis was attempted. Numerous attempts to condense (6) with 2-pyridinecarboxaldehyde …

Spectrophotometric And Microbiological Determination Of The Stability Of Sodium Ampicillin As Affected By Ph, Enrico Frank Raffanti

University of the Pacific Theses and Dissertations

The specific purpose of this investigation was to determine the effect of pH on the stability of ampicillin sodium for injection. Then, to correlate this information, a pH profile may be established to predict chemical stability with ampicillin sodium alone or when other drugs may be included in the admixture. With a pH profile the pharmacist could predict the length of time after which more than a 10 percent loss of activity would occur. Stability measurements were to be accomplished through a microbiological assay after adding ampicillin sodium to different buffer solutions. At the end of four hours, eight hours, …