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Design, Synthesis, and Evaluation of Novel Gram-Positive Antibiotics Part 2 University of Wisconsin Milwaukee UWM Digital Commons Theses and Dissertations 12-1-2016 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 University of Wisconsin-Milwaukee Follow this and additional works at: https://dc.uwm.edu/etd Part of the Organic Chemistry Commons Recommended Citation Witzigmann, Christopher Michael, "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" (2016). Theses and Dissertations. 1429. https://dc.uwm.edu/etd/1429 This Dissertation is brought to you for free and open access by UWM Digital Commons. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of UWM Digital Commons. For more information, please contact [email protected]. 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 by Christopher Michael Witzigmann A Dissertation Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in Chemistry at The University of Wisconsin-Milwaukee December 2016 ABSTRACT 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 by Christopher Michael Witzigmann The University of Wisconsin-Milwaukee, 2016 Under the Supervision of Distinguished Professor James M. Cook 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 analogs with minimum inhibitory concentrations (MICs) in pharmaceutically acceptable ranges and it is presumed that further SAR expansion will lead to even more potent compounds. Mechanism of action studies have shown that these compounds prove difficult to induce mutations in bacteria that lead to drug-resistance. This has made determination of the mechanism/mode of action difficult, and to date it is still not known, but is promising in that a lack of developed resistance may show that these compounds act on pathways that are novel and unlikely to form resistance. An enzyme catalyzed pathway involving tyrosinase is postulated as a plausible mechanism for these stilbenoid compounds. This process would involve the ii formation of quinones, which might be toxic to the bacteria, causing the observed bactericidal nature of these potent analogs. Further, this may explain some of the observed activity for a number of analogs synthesized in this study. The need for new antibiotics is clear, and these novel compounds represent a new scaffold for antibiotic drug discovery. Part 2. Dihydrobenzofurans are an important class of compounds, a number of which are natural products and/or biologically active. A new transition metal catalyzed pathway was developed to synthesize novel dihydrobenzofurans. This new process was modified from the Heck reaction developed in Part 1. Initially, the dihydrobenzofurans synthesized by the Heck mediated process were in very low yields. Optimization of the conditions for this reaction were successful in improving the conversion to nearly quantitative levels. A preliminary examination of the scope of the reactions indicated that a number of electron-rich aryl bromides were well tolerated and high yields for nearly all attempted aryl bromides were reported. The scope of vinyl arenes includes both aryl and heteroaryl vinylic compounds, many of which were conveniently synthesized from inexpensive starting materials. This reaction sequence is similar to work reported by Larock, however differs in a number of significant ways. Part 3. The α6 subunits of GABAA receptors exhibit a quite restricted regional distribution in the brain. They are predominantly expressed in the granule cells of the cerebellum, and in the cochlea nuclei. Our recent study revealed that the α6 GABAAR in the cerebellum plays an important role in controlling the sensorimotor gating function, a deficit of this function is manifested in several neuropsychiatric disorders, such as schizophrenia, tic disorders, attention deficit hyperactivity disorder, obsessive compulsive disorder. We have designed a series of pyrazoloquinolinone ligands that are functionally selective for α6β2,3γ2 GABAA receptors and are positive allosteric modulators at this subtype. Preliminary data show iii analogs such as Compound 6 and Compound 11 are effective in an animal model with sensorimotor gating deficit, reflecting the impairment of prepulse inhibition of the acoustic startle response (PPI) induced by methamphetamine. Recently, the α6 GABAAR was shown to be expressed in both neurons and satellite glia of the trigeminal ganglia. The α6 subunit positive neuronal cell bodies in the trigeminal ganglia project axons to the temporomandibular joint and likely to the trigeminal nucleus caudalis and upper cervical region (Vc–C1), and might modulate orofacial pain and inflammatory temporomandibular joint nociception and might modulate orofacial pain and inflammatory temporomandibular joint nociception. Rats with 30% knock down of the α6 subunit of GABAA receptors in trigeminal ganglia were hypersensitive to TMJ inflammation, measured by a prolong meal time. The prevalence of TMJ disorders in the United States is estimated at 4.6% and these disorders are the leading cause of chronic orofacial pain. Importantly, trigeminal ganglia also send projections to the trigeminal nucleus caudalis (TNC) and upper cervical region (Vc–C1), the trigeminal cervical complex. Activation of the TNC plays an important role in the neuropathogenesis of migraine. In an animal model of migraine, we have found a selective α6-GABAA receptor PAM, Compound 6, effectively decreased the number of activated neurons in the TNC induced by intracisteral (i.c.) injection of capsaicin. This suggests the potential of selective α6-GABAA receptor PAMs for the treatment of migraine. iv To my family and For my late grandfather Jack “Grandpa” Witzigmann v TABLE OF CONTENTS List of Figures .................................................................................................................................x List of Tables .............................................................................................................................. xiv List of Schemes ........................................................................................................................... xvi Part 1: Design, Synthesis, and Evaluation of Novel Gram-Positive Antibiotics .............. 1-191 Chapter 1: Introduction to Antibiotics .................................................................................2 I. History of Antibiotics ...........................................................................................2 II. Current Antibiotics ..............................................................................................4 1. Gentamicin ...............................................................................................4 2. Ampicillin ................................................................................................5 3. Oxacillin ...................................................................................................6 4. Ciprofloxacin ...........................................................................................7 5. Vancomycin .............................................................................................9 6. Erythromycin .........................................................................................10 7. Tetracycline............................................................................................11 8. Rifampin ................................................................................................12 III. The Need for New Antibiotics .........................................................................13 IV. Conclusion .......................................................................................................15 Chapter 2: Synthesis, Scale-up, and Biological Evaluation of SK-03-92 and a Small Series of Direct Analogs Based on an Interesting Stilbenoid Natural Product Scaffold ............................................................................................................16 I. Introduction and Background .............................................................................16 1. Natural Product Identification and Evaluation ......................................16
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