Global disease burden due to age related cognitive decline and dementias, especially Alzheimer’s disease, are a growing public health problem. Current treatments fail to completely prevent or cure dementia. A target of interest is the Insulin Regulated Aminopeptidase (IRAP) enzyme, inhibitors of IRAP have shown promise in preventing and reversing neurological degeneration associated with dementia. Structural information about IRAP when bound to an inhibitor is lacking, however, and future ligand design depends on knowledge of the mechanism of inhibition. We used long term MD simulations of IRAP bound to various ligands to investigate the conformational changes undergone by IRAP. PCA analysis was also used to investigate larger changes in the enzyme. A highly stable pose for a known spiro-oxindole inhibitor was found with key interactions between the ligand and SER546 and TYR 954, providing useful data for the design of future inhibitors of the IRAP enzyme.

Psilocybin is a hallucinogenic compound found in fungi and is currently evaluated inclinical trials for treatment of depression, anxiety and addiction. Psilocybin is aprodrug of the pharmacologically active metabolite, psilocin. The synthetic route topsilocybin relies on synthesizing psilocin from the starting material, 4-hydroxyindoleand latter converting psilocin into psilocybin by phosphorylation. The synthesis ofpsilocybin has been challenging because of the labile nature of the phosphorylationdibenzyl ester reagent and related intermediates. Several attempts to optimizepsilocybin synthesis have been published but there is still a need for furtherimprovements.The first aim of this project was to synthesize psilocybin using literature methods,while the second aim was to optimize the phosphorylation step with differentreagents and conditions.Initial studies focused on coupling the two-side chain carbon onto position three ofthe indole, this required protection of the hydroxyl group which was achieved byacylation in room temperature. With sufficient amount of dimethylamine solution, theamine addition reaction was investigated and resulted in a pure product. Thefollowing reduction with lithium aluminum hydride provided an unknown side-productinstead of psilocin.The first aim was successfully accomplished, up to psilocin, with pure intermediatesbut low yields. The second aim was not achieved due to lack of time and access tothe laboratory during covid-19 crisis. However, a literature survey of reagents andconditions for phosphorylation was performed which enables continuation of theproject.

No description available.

No description available.

A major gap in sexual assault casework is demonstrated when DNA is not recovered. Oftentimes, if DNA evidence is not present on the collection swabs, the sexual assault kit (SAK) is not further analyzed. Due to the "CSI effect," DNA is commonly understood as highly identifiable evidence, potentially leading to increased condom usage to eliminate or reduce DNA transfer during a sexual assault. Therefore, the analysis of condoms and sexual lubricants is pertinent. The purpose of this research is to develop analytical protocols to potentially connect unknown substances recovered in a SAK to known lubricant reference samples. Sexual lubricants were analyzed using Fourier transform infrared spectroscopy, gas chromatography-mass spectrometry, and direct analysis in real time-high resolution mass spectrometry. Analytical protocols were developed using 162 sexual lubricants comprised of bottled lubricants, condoms, and personal hygiene products. A statistical model was developed from 112 of the samples using hierarchical cluster analysis (HCA), principal component analysis (PCA), and linear discriminant analysis (LDA) to determine appropriate sample groupings that resulted in at least 97% accurate classification for each instrument. Assigned truth classes for the remaining 50 samples were developed using Pearson correlation coefficients (PCCs) to predict classification accuracy for unknown samples. The FTIR data resulted in a 96% accurate prediction, 54% for GC-MS, and 42% for DART-HRMS, showing the need for expansion of the sample set in future analysis. Potential storage conditions of SAK swabs were evaluated using PCCs to identify optimal swab storage conditions, which was determined to be a humidity-controlled environment around 22 °C. Then, post-coital swab samples from volunteers using an unknown condom were analyzed using the developed protocols. The data was analyzed using PCC, PCA, and LDA to compare the classification to the "ground truth" of the sample to determine potential applications of this research in SAK analysis.

Magnetic materials are currently being developed in the areas of pharmacology and medicinal chemistry for use in applications such as drug delivery and magnetic resonance imaging. Magnetic fluids are being used in audio equipment and hard disk drives. Their suspension in a particular fluid is promoted by the adsorption or reaction of steric or electrostatic stabilizers, which are appropriate for the particular medium. Critical to the success of these magnetic fluids is the development of the steric stabilizers, which must prevent the coagulation of the metal particles. Polymeric materials are one of the most suitable nonmagnetic media to disperse the magnetic nanoparticles, forming polymeric nanocomposites in ferrofluids. We have developed strategies in molecular nanoscience to design polymeric systems for stabilization of magnetic nanoparticles. Ring opening metathesis polymerization (ROMP) was used to prepare a series of novel, well-defined diblock copolymers of bicyclo[2.2.1]hept-5-ene 2-carboxylic acid 2-cyanoethyl ester and bicyclo[2.2.1]hept-2-ene, consisting of both anchoring and steric stabilizing blocks. Both ester and cyano groups were incorporated into the polymers to chelate and stabilize the iron oxide magnetic nanoparticles. These polynorbornene-based copolymers were characterized by GPC, along with 1H NMR, FTIR, DSC, and TGA. Using diblock copolymers as stabilizers, nanostructured maghemite (γ-Fe2O3) magnetic ferrofluids were prepared in toluene or cyclohexanone via thermal decomposition of Fe(CO)5 and then the oxidation of iron nanoparticles. Transmission electron microscopic (TEM) images showed a highly crystalline structure of the γ-Fe2O3 nanoparticles, with average particle size varying from 5 to 7 nm. Polymer films containing iron oxide nanoclusters were also prepared from the diblock copolymers. For comparison, a commercial triblock copolymer (BASF PluronicR F127) surfactant was used to prepare stabilized ferrofluids. In addition to γ-Fe2O3 nanoparticles, other types of magnetic nanoparticles, such as FePt, were investigated using this triblock copolymer as a stabilizer. The results indicated that the norbornene diblock copolymers could also be used for the preparation of FePt stabilized magnetic ferrofluids in the future research work.

Adenosine receptors (ARs) are a family belonging to the GPCR superfamily, involved with multiple physiological processes and widely distributed throughout the body. In this study, we focus on the A3 AR due to its vast scale applications in various pathophysiological conditions such as inflammation, pain, allergic asthma, and cancer chemotherapy. We report the validation of the binding mode of A3 AR antagonists, through a comprehensive in-silico mutagenesis study using free energy perturbations, reproducing prior experimental site-directed mutagenesis data for A3 AR antagonists. After validating the antagonist binding mode, we performed an extensive in-silico site-directed mutagenesis study on the hA3 AR using potent, selective, and structurally simple A3 AR antagonist based on the N-(2,6-diarylpyrimidin-4- yl)acetamide scaffold (pyrimidine core). The results of this study will be used to design in- vitro site-directed mutagenesis performed by collaborators (University of Barcelona). Once the binding mode of this scaffold is validated, it will be the basis for the design of compounds with two well-defined functionalities: a fluorophore moiety and bivalent ligands that target A3 dimers. The discovery of novel mutations on the hA3 AR is a step forward in the development of both chemically simple, potent, and selective A3 AR antagonists as well as in the characterization and crystallization of the A3 AR.

Thesis (M.Pharm.)--University of the Witwatersrand, Faculty of Health Sciences, 2013. / Sexually transmitted infections (STIs) are a global concern and more specifically southern Africa has seen a tremendous upsurge in infection rates. KwaZulu-Natal is the province found to have the highest Human Immunodeficiency Virus and STI infection rates. From an ethnobotanical study conducted specifically in northern Maputaland (Mabibi, Tshongwe, Mseleni and Mbazwana), it was found that the lay people most often used plants in various combinations for the treatment of STI related symptoms. The use of these plant combinations were thus antimicrobially investigated and the toxicity properties determined. The dichloromethane: methanol (organic) and aqueous extracts were prepared for each plant in situ using collected ground dried plant material. The plants (individually and in combination) were investigated for toxic potential using the 3-[4,5-dimethyl-2-thiazol-yl]-2,5-diphenyl-2H-tetrazolium bromide (MTT) cellular viability assay on the human kidney epithelial (Graham) cell line. The antimicrobial activities for each sample, as well as for each combination, were then further investigated using the minimum inhibitory concentration (MIC) assay. The six STI pathogens investigated in this study were Candida albicans (ATCC 10321), Ureaplasma urealyticum (clinical strain), Oligella ureolytica (ATCC 43534), Gardnerella vaginalis (ATCC 14018), Trichomonas vaginalis (clinical strain) and Neisseria gonnorhoeae (ATCC 19424).

As ferramentas computacionais de modelagem molecular e de QSAR estão integradas ao processo de planejamento de fármacos na busca inesgotável por novas moléculas bioativas de elevado interesse terapêutico. O trabalho em Química Medicinal realizado nesta dissertação de mestrado envolveu o estudo das relações entre a estrutura e atividade de inibidores da enzima purina nucleosídeo fosforilase (PNP) bovina e de Schistosoma mansoni. A potência de uma série de inibidores da PNP de S. mansoni foi determinada experimentalmente através da medida de valores de 1C50, empregando um ensaio cinético padronizado e validado. Conjuntos de dados padrões para inibidores da enzima PNP bovina e de S. mansoni foram organizados, contendo os dados de estrutura e atividade correspondentes. Estes conjuntos formaram a base científica para o desenvolvimento dos modelos preditivos de QSAR 2D, empregando o método holograma QSAR. Os modelos finais de HQSAR desenvolvidos possuem alta consistência interna e externa, apresentando bom poder preditivo. Estes modelos, em conjunto com as informações obtidas dos mapas de contribuição de HQSAR, são guias químico-medicinais importantes no planejamento de inibidores mais potentes e seletivos, candidatos a protótipos de novos fármacos na quimioterapia segura das doenças alvo deste trabalho / Computational tools for molecular modeling and QSAR are well-integrated into the drug design process in the search for new bioactive molecules of significant therapeutic interest. The Medicinal Chemistry work done in this dissertation involved structure-activity studies of inhibitors of bovine and Shistosoma mansoni purine nucleoside phosphorylase (PNP). The potency of a series of S. mansoni inhibitors was experimentally determined through measurements of IC50 values, employing a standard validated kinetic assay. Data sets for bovine and S. mansoni PNP were organized, encompassing the structural information and corresponding biological data. These data sets established the scientific basis for the development of the predictive QSAR models using the hologram QSAR method. The final HQSAR models generated possess both good internal and external consistency with good correlative and predictive power. These models and the information obtained from the HQSAR contribution maps should be useful in guiding future medicinal chemistry efforts designed to discover novel potent and selective inhibitors as drug candidates for the chemotherapy of the target diseases of this work

Thesis (M.S.)--University of Texas at El Paso, 2008. / Title from title screen. Vita. CD-ROM. Includes bibliographical references. Also available online.