Browsing by Author "Dr. Bruce Novak, Committee Member"

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The Development of Ageliferin Inspired Small Molecules as Antibiofilm and Antibacterial Agents against Multidrug Resistant Bacterial Pathogens
(2009-07-22) Huigens, Robert William III; Dr. Christian Melander, Committee Chair; Dr. Reza Ghiladi, Committee Member; Dr. Bruce Novak, Committee Member; Dr. Daniel L. Comins, Committee Member
ABSTRACT HUIGENS III, ROBERT WILLIAM. The Development of Ageliferin Inspired Small Molecules as Antibiofilm and Antibacterial Agents against Multidrug Resistant Bacterial Pathogens. (Under the direction of Dr. Christian Melander.) The development of ageliferin inspired small molecules is described herein. These analogues collectively demonstrated non-toxic biofilm inhibition, biofilm dispersion activity and antibiotic activity. Biofilm-mediated infections pose a serious threat to due to increased drug-resistance to antibiotics and host immune responses. TAGE and CAGE were the first synthetic 2-aminoimidazoles to demonstrate the ability to inhibit biofilm formation against Pseudomonas aeruginosa. In growth curve analysis, TAGE demonstrated less toxicity towards planktonic P. aeruginosa than CAGE. These two small molecules also dispersed preformed PAO1 and PA14 biofilms. TAGE was also evaluated in confocal microscopy experiments and demonstrated the ability to disperse PAO1:gfp biofilms under continuous flow conditions as well as demonstrating non-toxic effects towards bacterial cells within a biofilm in DEAD/LIVE staining. BromoTAGE and DibromoTAGE, two TAGE-Pyrrole analogues, demonstrated increased biofilm inhibition compared to TAGE or CAGE against P. aeruginosa strains. These analogues were also active against Acinetobacter baumannii and Staphylococcus aureus biofilm formation. The parent structure, TAGE, was found to be inactive against these strains of bacteria. Although these pyrrole analogues of TAGE were very effective in biofilm inhibition screens, they demonstrated little activity in biofilm dispersion activity. A 21-membered library of TAGE-Triazoles was then synthesized and screened for biofilm inhibition activity. The majority of this library demonstrated non-toxic, biofilm inhibition against A. baumannii. Various members from this collection of TAGE-Triazoles were also active against S. aureus and P. aeruginosa in biofilm inhibition assays. Dibromopyrrole TAGE-Triazole demonstrated very potent biofilm inhibition activity against S. aureus (IC50 = 141 Ã‚Â± 28 nM). A diverse library of 2-aminobenzimidazoles (2ABIs) was synthesized and found to possess impressive antibiotic activity against several strains of multidrug-resistant bacteria. Methicillin-resistant Staphylococcus aureus was unable to demonstrate resistance against the active members from this library. The active 2-aminobenzimidazoles also demonstrated promising antibiotic activity against several clinical isolates of A. baumannii. Active 2ABIs also demonstrated broad spectrum antibiotic activity against several other bacteria.
Small Molecule Control of Biological Function
(2008-08-27) Ballard, Thomas Eric Jr.; Dr. Christian Melander, Committee Chair; Dr. Bruce Novak, Committee Member; Dr. Daniel Comins, Committee Member; Dr. David Shultz, Committee Member
Substituent Effects on Exchange Coupling: Controlling the Interactions between Unpaired Electrons
(2007-08-07) Coote, Tashni-Ann; Dr. Chris Gorman, Committee Member; Dr. Tatyana Smirnova, Committee Member; Dr. Bruce Novak, Committee Member; Dr. David A. Shultz, Committee Chair
Design, synthesis, and characterization of novel high-spin species are critical for advancing the field of molecular magnetism, and subsequently creating new magnetic materials. As a means of grasping an understanding of how it is that one can control the electronic, hence magnetic interactions within a high-spin species, this study focuses on structure- property relationships in a series of bis(semiquinone) biradicals. The biradical moiety is the simplest of exchange-coupled systems. As electron-withdrawing, -donating and neutral substituents are placed on the coupler or spin carrier fragment of the biradicals under study, it is shown that there is a substituent effect operating within the series of ferromagnetically coupled m-phenylene bis(semiquinone) moieties.
Total Synthesis of (+)-Hyperaspine, Advances Toward the Total Synthesis of Spirolucidine, and [2+2]-Photochemical Cycloadditions of 2,3-Dihydro-4-Pyridones
(2009-01-05) Sahn, James Jeffrey; Dr. Daniel Lee Comins, Committee Chair; Dr. Alex Deiters, Committee Member; Dr. Bruce Novak, Committee Member; Dr. Christian Melander, Committee Member
The ladybug alkaloid, (+)-hyperaspine, was synthesized in 6 steps and 21% overall yield. Utilizing Cs2CO3 and CH2Br2, a novel entry into the 3,4,4a,5-tetrahydropyrido[1,2-c][1,3]oxazin-6(1H)-one ring system was developed. The synthesis showcases a stereoselective dissolving-metal reduction, which provided the requisite equatorial alcohol that was rapidly advanced to the natural product. Significant progress has been made towards the total synthesis of the Lycopodium alkaloid, spirolucidine. Implementing a convergent approach to the natural product, zone A was synthesized and united with zone B. Subsequent elaboration of the A-B fragment afforded the N-Boc derivative for an impending ortho-lithiation. Additionally, the racemic, desmethyl zone C was prepared from its carboxylic acid precursor via the Barton ester. Finally, the Negishi cross-coupling reaction was investigated for the union of racemic, desmethyl zone C with a zone B surrogate. The intramolecular [2+2]-photochemical cycloaddition of 2,3-dihydro-4-pyridones proceeded in good yield with excellent stereocontrol. When the photoadducts were treated with SmI2, different mechanistic pathways ensued. The lower homologue underwent a dual ring opening/reduction, rendering a cis 2,6-disubstituted piperidinol. Exposure of the higher homologue to SmI2 resulted in homolytic Î²-cleavage, which afforded an azaspiro[5.5]undecane.