Medicinal and Pharmaceutical Chemistry Commons^™

Synthesizing Modified Polymeric Nanoparticles For Biofilm Inhibition, Antibiotic Encapsulation, And Specific Targeting Against Pseudomonas Aeruginosa, Logan Schnorbus

Theses and Dissertations

Widespread usage of antibiotics is a growing concern due to antibiotic resistance development in bacteria. This is due to common use of antibiotics in agricultural, livestock, and clinical usage. Antibiotic resistance is developing at a rate in which it is outpacing new drugs on the market. New strategies in drug development are necessary to combat the increasing resistance. We designed several motifs of sugar-modified nanoparticles to inhibit the biofilm formation of Pseudomonas aeruginosa.

P. aeruginosa is an opportunistic pathogenic bacterium that is responsible for common life-threatening infection in hospitals. This gram-negative opportunistic pathogenic bacterium infects hosts with compromised immune systems …

An In Silico Study Of Small Molecule Anti-Cancer Agents Targeting Dna G-Quadruplexes, Holli-Joi Sullivan

Theses and Dissertations

Free ligand binding molecular dynamic simulations are a powerful tool used to probe the ligand binding process, mechanism and pathway and the insight gained can help expedite the early stages of drug discovery. Using these methods, we model the binding of two small molecule anti-cancer agents BRACO19 and CX-5461 to a variety of DNA G-quadruplexes (G4s) and a DNA Duplex. The first study focuses on the binding of BRACO19 to three different topological folds (parallel, anti-parallel and hybrid) of the human telomeric G4s. Our detailed analysis identified the most stable binding modes were end stacking and groove binding for the …

Development Of A Screening Assay For Type Iii Secretion System Inhibitors And High Throughput Screening Campaign Of Inhibitors Of Prp Of Staphylococcus Aureus, Heather A. Pendergrass

Theses and Dissertations

Antibiotics inhibit the growth or survival of bacteria by targeting their essential functions.¹ Due to weaknesses in traditional antibiotics and the increasing prevalence of antibiotic resistance genes, virulence factors are being targeted for therapeutic treatment of bacterial infection.² We have developed an assay to quantify and observe type III secretion system (T3SS) activity. The type III secretion system (T3SS) is a virulence factor present in some Gram-negative pathogens including enteropathogenic and enterohemorrhagic E. coli (EPEC and EHEC, respectively),³ and others.^4–9 The T3SS between EPEC and EHEC are highly conserved and share over 90% sequence identity with …

Synthesizing Galactose Modified Polymeric Nanoparticles For Biofilm Inhibition Of Pseudomonas Aeruginosa, Tyler R. Flockton

Theses and Dissertations

Treating patients with antibiotics is becoming harder with the increase in antibiotic resistance. This is due to the widespread antibiotic use in clinical and agricultural settings. With antibiotic resistance outpacing new drugs making it to the market, developing new options to treat bacterial infections is and will be important. We created sugar modified nanoparticles to inhibit the biofilm formation of Pseudomonas aeruginosa.

P. aeruginosa is a gram-negative opportunistic pathogen that infects its host that has a compromised immune system. This makes it one of the most significant bacterial infection in hospitals. P. aeruginosa uses biofilms as an attack mechanism …

Synthesis Of Betulinic Acid Via Baylis-Hillman Reaction, Sai Krishna Kommineni

Theses and Dissertations

Betulin is readily isolated from the bark of birch trees using simple extraction techniques and this molecule as well as its derivatives (eg. betulinic acid) exhibit impressive levels of biological activity. While it is naturally available and shows selective toxicity towards certain cancers, betulin suffers from a general lack of solubility in aqueous conditions. In this regard, we took up a project involving the synthesis of conjugates of betulin with improved solubility characteristics and we were able to identify a series of compounds that showed cytotoxicity against breast and pancreatic cancer cells.

This thesis describes our efforts on the development …

Development Of Functionalized Imidazoles As Potential Therapeutical Agents, Drew Christopher Morgan

Theses and Dissertations

Imidazoles are heterocyclic small molecules that play a major role in medicinal chemistry and drug discovery. There are several drugs in the market which contain imidazoles as the pharmacophore. Metronidazole, an imidazole containing compound, is a prominent antibiotic and antiprotozoal medication used for the treatment of a variety of infections such as amoebiasis, trichomoniasis, bacterial vaginosis, etc. The current work involves the synthesis of small molecule libraries of imidazoles derived from metronidazole using Baylis-Hillman (BH) reaction. BH reaction is a carbon-carbon bond forming reaction and involves the coupling of aldehydes or imines with activated alkenes such as acrylates, acrolein, or …

Functionalized Heterocyclics As Potential Therapeutics, Anupama Indukuri

Theses and Dissertations

Heterocyclic compounds play an important role in pharmaceutical drug development. Several natural products and biologically active compounds contain heterocyclic motifs in them. Multicomponent coupling reactions offer an excellent platform for the synthesis of diverse libraries of heterocyclic compounds. We have been working on the synthesis of novel heterocyclic small molecules utilizing reactions such as Baylis-Hillman reaction, Passerini reaction, Click reaction, reductive amination aldol condensation, etc.

In the current project, we prepared three series of heterocyclic compounds using Passerini and Baylis-Hillman reactions as key steps. Owing to the importance of heterocyclic chemistry in drug discovery and the ease of synthesis, the …

Modification And Characterization Of Chloro-Sugar Derivatives As Anti-Bacterial Agents, Mansi Jani

Theses and Dissertations

Sucralose is an artificial sugar substitute which is most commonly used sweetener among other artificial sweeteners. It is derived from sucrose through a complex chemical process that selectively substitutes three atoms of chlorine for three hydroxyl groups on sucrose molecule, which have shown some inhibition of bacterial growth in gut. The goal of the project was to substitute halide in sucralose in a way that it sustains potential anti-bacterial activity along with sweetening effect, which can be then incorporated into mouthwash formulation. Sucralose is very stable molecule and it also has other physico-chemical advantages which are suitable for our anticipated …

Synthesis Of Novel Library Of Cyanopyrrolidinyl Beta-Amino Alcohols And Matrine Alkaloids, Xiaotian Chen

Theses and Dissertations

Cyanopyrrolidines and beta-Amino alcohols are molecular scaffolds that are highly found in commercially available drugs. We developed a multi-step synthetic method to form a novel library of compounds as inhibitors that share both scaffolds toward potent and selective diabetes therapeutics. Despite the ease for the synthesis of Cyanopyrrolidines, the difficulty of forming high selective beta-Amino alcohols is challenging. We successfully find the best condition for the preference of highly selective mono-alkylation and double-alkylation products and produce them with high yield.

Matrine is an alkaloid found in plants from the genus Sophora and can produce some pharmacological effects such as anti-cancer …

Structure-Activity Relationship Studies Of Synthetic Cathinones And Related Agents, Rachel A. Davies

Theses and Dissertations

Synthetic cathinones and related agents represent an international drug abuse problem, and at the same time an important class of clinically useful compounds. Structure-activity relationship studies are needed to elucidate molecular features underlying the pharmacology of these agents. Illicit methcathinone (i.e., MCAT), the prototype of the synthetic cathinone class, exists as a racemic mixture. Though the differences in potency and target selectivity between the positional and optical isomers of synthetic cathinones and related agents have been demonstrated to have important implications for abuse and therapeutic potential, the two MCAT isomers have never been directly compared at their molecular targets: the …

Inhibition Of Cancer Stem Cells By Glycosaminoglycan Mimetics, Connor P. O'Hara

Theses and Dissertations

Connor O’Hara July 29, 2019

Inhibition of Cancer Stem Cells by Glycosaminoglycan Mimetics

In the United States cancer is the second leading cause of death, with colorectal cancer (CRC) being the third deadliest cancer and expected to cause over 51,000 fatalities in 2019 alone.¹ The current standard of care for CRC depends largely on the staging, location, and presence of metastasis.² As the tumor grows and invades nearby lymph tissue and blood vessels, CRC has the opportunity to invade not only nearby tissue but also metastasize into the liver and lung (most commonly).³ The 5-year survival rate …

Development Of Bivalent Ligands Targeting The Putative Mu Opioid Receptor And Chemokine Receptor Cxcr4 Heterodimer, Bethany A. Reinecke

Theses and Dissertations

Human immunodeficiency virus (HIV) and opioid abuse have been described as synergistic epidemics. Pharmacologically, it has been found that opioids have the capacity to enhance HIV infection and replication. Research has shown that activation of the mu-opioid receptor (MOR) elevates the expression of the HIV-1 entry co-receptor CXCR4 on T-lymphocytes in the peripheral nervous system, thus allowing for enhanced viral entry and invasion. Although the exact mechanism for opioid modulation of CXCR4 expression and subsequent exacerbation of HIV is unknown, several hypotheses exist. One hypothesis is that MOR and CXCR4 are functionally interacting through the formation of a heterodimer. This …

Design, Synthesis And Pharmacological Characterization Of Potential Mu Opioid Receptor Selective Ligands, Abhishek S. Kulkarni

Theses and Dissertations

Selective Mu Opioid Receptor (MOR) antagonists possess immense potential in the treatment of opioid abuse/addiction. Utilizing the “message-address” concept, our laboratory reported a novel, reversible, non-peptide MOR selective antagonist 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(4՛-pyridyl)carboxamido]morphinan (NAP). Molecular modeling studies revealed that the selectivity of NAP for the MOR is because of a π-π stacking interaction of its pyridine ring with the Trp318residue in theMOR. Pharmacological characterization showed that NAP is a P-glycoprotein substrate, thereby limiting its use in the treatment of opioid abuse/addiction. Thus, to modify NAP, we replaced the pyridine ring with its isosteric counterpart thiophene. Isosteric replacement …

Synthesis And Cytotoxicity Of Azaheterocyclic Compounds, Keyur M. Pandya

Theses and Dissertations

Multicomponent coupling reactions (MCRs) have been known for a long time and one such reaction that utilizes isocyanides is Passerini reaction. It is a powerful tool to synthesize libraries of different compounds. Azaheterocyclic compounds play an important role in medicinal chemistry. Motifs such as imidazoles, piperazines, pyrazoles, pyridines, triazoles, etc. are routinely observed in several compounds of pharmacological interest. Several natural products also contain these motifs in them. We have undertaken a library synthesis of heterocyclic molecules driven by our group's long-standing interest of synthesizing medicinally relevant small molecules employing green chemistry techniques.

This thesis details our efforts on the …

A Study Of Albendazole And Artemisinin Drugs Under Electrochemical Oxidation, Zahilis A. Mazzochette

Theses and Dissertations

This work is aimed to investigate the metabolic behavior of albendazole and artemisinin. The electrochemical oxidation and reduction of these drugs were performed on electrode materials to mimic their metabolism in vivo using cyclic voltammetry and bulk electrolysis analysis. The oxidation of albendazole on gold electrode surface yielded albendazole sulfoxide and albendazole sulfone which are the main metabolites of this drug in vivo. Reduction of artemisinin on glassy carbon (GC) electrode surface yielded dihydroartemisinin and deoxy artemisinin. The formation of these products was monitored using liquid chromatography and mass spectrometry techniques. The redox processes for both drugs were shown to …

Novel Aminobenzoboroxoles As Potential Anti-Cancer Agents, Bhawankumar Pravinchandra Patel

Theses and Dissertations

Boronic acids are a promising class of compounds due to their wide range of applications in medicinal and materials chemistry, and as coupling agents in organic synthesis. B-hydroxy-1,2-oxaborolanes (benzoboroxoles) are categorized as cyclic boronic acid derivatives and they are very important organic molecules because of their metabolic stability and their ability to undergo important C-C bond forming reactions such as Suzuki cross coupling. Several of these cyclic boronic acids are found to have promising pharmacological properties as antifungal, antimalarial and anti-inflammatory agents. However, based on the literature reports, synthesis of highly functionalized benzoboroxoles is typically cumbersome and not very conducive …

Galantamine's Deconstruction In The Quest Of A Pam Pharmacophore, Malaika Argade

Theses and Dissertations

Alzheimer’s disease is a progressive neurodegenerative disorder generally affecting people above the age of 65 years. Even though the pathophysiological hallmarks of AD were established more than a hundred years ago, there is yet to be a drug that can stop its characteristic neuronal damage. Of the five currently FDA-approved drugs, galantamine has a unique mechanism of action. Apart from being an AChE inhibitor, galantamine can effectively potentiate (positive allosteric modulator) the effect of agonists at nAChRs at concentrations lower than those required for its action as an AChE inhibitor. Perhaps the clinical benefits observed with galantamine are associated mainly …

Glycosaminoglycan Lyases In The Preparation Of Oligosaccharides, Alhumaidi B. Alabbas

Theses and Dissertations

Glycosaminoglycans are heterogeneous polysaccharides that mediate important biological functions. There has been considerable interest in deciphering the precise GAG sequences that are responsible for protein interactions. In fact, several GAG oligosaccharides have been discovered to date as targeting proteins with higher level of specificity. Yet, it has been difficult to develop GAG oligosaccharides as drugs. One of the key reasons for this state of art is that GAG synthesis is extremely challenging and is highly structure-specific. Thus, much of the biology and pharmacology of GAG remains unknown and unexploited to date.

An alternative approach is to prepare GAG oligosaccharides using …

Elucidation Of Substrate Binding Interactions For Human Organic Cation Transporters 1 (Slc22a1) And 2 (Slc22a2) Using In Silico Homology Modeling In Conjunction With In Vitro Site-Directed Mutagenesis And Kinetic Analysis, Raymond E. Lai

Theses and Dissertations

The organic cation transporters (OCTs) play a critical role in the absorption, distribution and elimination of many drugs, hormones, herbal medicines, and environmental toxins. Given the broad substrate specificity of OCTs, they fall victim to the high susceptibility for contributing to harmful drug-drug interactions. Further defining how human (h)OCTs mechanistically bind to its broad array of substrates will provide significant insight to the understanding and prediction of drug-drug interactions in polypharmacy patients and the advancement of future rational drug design for therapeutics targeting OCTs. The goal of the current study was to elucidate the critical amino acid residues for transporter-substrate …

Rational Design Of Allosteric Modulators Of Hemoglobin As Dual Acting Antisickling Agents, Piyusha P. Pagare

Theses and Dissertations

Intracellular polymerization of deoxygenated sickle hemoglobin (Hb S) remains the principal cause of the pathophysiology associated with sickle cell disease (SCD). Naturally occurring and synthetic allosteric effectors of hemoglobin (AEH) have been investigated as potential therapeutic agents for the treatment of SCD. Several aromatic aldehydes, including vanillin, have been studied previously as AEHs for their antisickling activities. Specifically, these compounds form Schiff- base adduct with Hb to stabilize the oxygenated (R) state, increase Hb affinity for O2 and concomitantly prevent the hypoxia-induced primary pathophysiology of Hb S polymerization and RBC sickling, in turn, ameliorating several of the cascading secondary adverse …

Development Of Small Molecule Neuroprotectants, Ashley Boice

Theses and Dissertations

Neurodegenerative diseases are a class of conditions that lead to progressive atrophy of different parts of the central nervous system (CNS). These diseases lead to devastating clinical outcomes to patients and give rise to an enormous socio-economical burden on society.¹ One commonality among some of the most well-known neurodegenerative disorders, e.g. Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS), is neuroinflammation.^2-4 Neuroinflammation stems from interactions of the innate immune system with toxins and insults to the central nervous system. In the case of irremovable or chronic insults and toxins, this leads to chronic damaging …

Chemical Probes For Protein Α-N-Terminal Methylation, Brianna D. Mackie

Theses and Dissertations

While protein α-N-terminal methylation has been known for nearly four decades since it was first uncovered on bacteria ribosomal proteins L33, the function of this modification is still not entirely understood. Recent discoveries have demonstrated α-N-terminal methylation is essential to stabilize the interactions between regulator of chromosome condensation 1 (RCC1) and chromatin during mitosis, to localize and enhance the interaction of centromere proteins (CENPs) with chromatin, and to facilitate the recruitment of DNA damage-binding protein 2 (DDB2) to DNA damage foci. Identification of N-terminal methyltransferase 1 (NTMT1) unveiled the eukaryotic methylation writer for protein α-N-termini. In addition, NTMT2 that shares …

Structure-Activity Relationship Studies Of Bupropion And Related 3-Substituted Methcathinone Analogues At Monoamine Transporters, Abdelrahman R. Shalabi

Theses and Dissertations

The khat plant, catha edulis, has been abused for some time in the Middle East and the African horn for its short-term stimulant effects. However, it was not until 1975 when cathinone, β-ketoamphetamine, was identified as the major stimulant component of khat. Structural analogues of cathinone, synthetic cathinones, are new psychoactive substances available on the clandestine market of numerous countries including the USA. Abuse of these new illicit stimulants is a worldwide growing health concern which necessitates the investigation of the pharmacological properties of these new drugs of abuse. The abuse liabilities of these compounds seem to be related …

Design, Synthesis, And Biological Screening Of Selective Mu Opioid Receptor Ligands As Potential Treatments For Opioid Addiction, Samuel Obeng

Theses and Dissertations

Today, more Americans die each year because of drug overdoses than are killed in motor vehicle accidents. In fact, in 2015, more than 33,000 individuals died due to an overdose of heroin or prescription opioids. Sadly, 40-60 % of patients on current opioid addiction treatment medications relapse. Studies have shown that the addiction/abuse liability of opioids are abolished in mu opioid receptor (MOR) knock-out mice; this indicates that the addiction and abuse liability of opioids are mainly mediated through MOR. Utilizing the “message-address concept”, the our laboratory reported a novel non-peptide, reversible MOR selective ligand 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α (isoquinoline-3-carboxamido)morphinan (NAQ). Molecular modeling …

Study Of Molecular Interactions Of Glycosaminoglycans And Glycosaminoglycan Mimetics With Their Protein Targets, Daniel K. Afosah

Theses and Dissertations

Glycosaminoglycans (GAGs) are complex linear chain carbohydrate molecules found on virtually all animal cell surfaces. Owing to their negatively charged nature, GAGs interact with a number of different proteins. Thus, although they have great potential as therapeutic agents, their apparent promiscuous interactions increase their side effect risk. GAG mimetics, including GAG oligosaccharides and non-saccharide GAG mimetics (NSGMs) are viable approaches to address this. This work discusses sulfated benzofuran thrombin inhibitors with submaximal protease inhibition, sulfated diflavonoid inhibitors of plasmin and GAG oligosaccharides with selectivity for human neutrophil elastase (HNE).

Anticoagulants are very important for the treatment of thrombotic diseases. The …

Probing Allosteric, Partial Inhibition Of Thrombin Using Novel Anticoagulants, Stephen S. Verespy Iii

Theses and Dissertations

Thrombin is the key protease that regulates hemostasis; the delicate balance between procoagulation and anticoagulation of blood. In clotting disorders, like deep vein thrombosis or pulmonary embolism, procoagulation is up-regulated, but propagation of clotting can be inhibited with drugs targeting the proteases involved, like thrombin. Such drugs however, have serious side effects (e.g., excessive bleeding) and some require monitoring during the course of treatment. The reason for these side effects is the mechanism by which the drugs’ act. The two major mechanisms are direct orthosteric and indirect allosteric inhibition, which will completely abolish the protease’s activity. Herein we sought an …

Exploring The Concept Of Human Oct3 Inhibitors As A Novel Class Of Antidepressants, Kavita A. Iyer

Theses and Dissertations

The Dukat laboratory developed 2-amino-6-chloro-3,4-dihydroquinazoline (A6CDQ) as a 5-HT₃ receptor ligand. A6CDQ and one of its positional isomers, the 7-chloro analog A7CDQ, produced antidepressant-like effects in the mouse tail suspension test (TST). We investigated and systematically ruled out a solely 5-HT₃ receptor or hSERT mediated mechanism of antidepressant-like effect for both A6CDQ and A7CDQ.

The role of organic cation transporter 3 (OCT3) as an alternative mechanism in the regulation of neurotransmitters including serotonin (5-HT) and the therapeutic potential of targeting hOCT3 to achieve antidepressant effects has been established. By virtue of possessing protonatable nitrogen atoms, 2-aminodihyroquinazolines could potentially …

The Effects Of Amixicile, A Pyruvate Ferredoxin Oxidoreductase Inhibitor, On Oral Treponemes, Lucas A. Reed

Theses and Dissertations

Periodontal disease (PD) is a polymicrobial infection characterized by inflammation of the gingiva, alveolar bone resorption, and tooth loss (edentulism). Treponema denticola along with Porphyromonas gingivalis and Tannerella forsythia are among the “Red Complex” and are main etiological agents in PD. Treponemes are a member of the Spirochaeta phylum and are obligate anaerobes, that express pyruvate ferredoxin oxidoreductase (PFOR). The enzyme catalyzes the oxidation of pyruvate to acetyl-CoA and reduced ferredoxin. Amixicile is a novel bacteriostatic derivative of nitazoxanide and an inhibitor of PFOR. In light of the fact that Treponemes express PFOR, this study was conducted to investigate the …

Design And Structure-Activity Relationship Of Small Molecule C-Terminal Binding Protein (Ctbp) Inhibitors And Investigation Of The Scope Of Palladium Multi-Walled Carbon Nanotubes (Pd-Mwcnt) Catalyst In C–H Activation Reactions, Sudha Korwar

Theses and Dissertations

C-terminal binding proteins (CtBPs) are transcriptional co-repressors involved in developmental processes, and also implicated in a number of breast, ovarian, colon cancers, and resistance against cancer chemotherapy. CtBP is a validated novel potential anti-cancer target. In this project we sought to develop potent and selective small-molecule inhibitors of CtBP. Using a combination of classical medicinal chemistry and modern computational approaches, we designed a potent inhibitor HIPP (hydroxyimino-3-phenylpropanoic acid) that showed an IC₅₀ of 0.24 μM against recombinant CtBP. Further elucidation of the structure-activity relationship (SAR) of HIPP led to the design of more potent inhibitors 3-Cl HIPP (CtBP IC …

Curcumin/Melatonin Hybrids As Neuroprotective Agents For Alzheimer's Disease, John Saathoff

Theses and Dissertations

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia, affecting ~5.2 million Americans. Current FDA approved medications provide mainly symptomatic relief and there are no agents available to delay or cure this disease. Multiple factors such as amyloid-β aggregates, dyshomeostasis of biometals, oxidative stress, and neuroinflammation have been implicated in the development of AD. Even though significant advances have been made in understanding the mechanisms leading to AD, the exact etiology still remains elusive. Given AD’s multifactorial nature, a multifunctional strategy of small molecule design would help to identify novel chemical templates. Recently our lab …