Division of Medicinal Chemistry Abstracts-235th ACS National ...

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MEDI 32 Synthesis of novel triazole-bearing nitroimidazoles with improved antimicrobial activity against the protozoan pathogen Giardia Carlos A. Valdez 1 , Jaroslaw Kalisiak 1 , Jonathan C. Tripp 1 , Barbara Davids 2 , Frances Gillin 2 , Valery V. Fokin 1 , K. Barry Sharpless 1 , and Lars Eckmann 2 . (1) Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, CA 92037, (2) Department of Pathology and Medicine, University of California, San Diego, La Jolla, CA 92093 The protozoan enteric parasite, Giardia lamblia, infects hundred of millions in the world and is a major cause of waterborne diarrheal disease. The infection is primarily treated with metronidazole (Mz), a compound belonging to a class known as the 5-nitroimidazole antibiotics. Standard treatment with Mz is safe and effective in 80-90% of cases, but treatment failure is common and Mz-resistant strains of the parasite have been reported. To overcome resistance, new and more potent antigiardial drugs are in needed. Herein, we describe the use of click chemistry, more specifically the copper(I)-catalyzed azide-alkyne cycloaddition reaction, to rapidly and efficiently generate a library of triazole-bearing 5-nitroimidazoles for use against the parasite and its resistant variants. The synthesis and biological evaluation of a number of novel 5-nitroimidazolides will be presented. MEDI 33 Synthesis and biological activity of antagonists of AI-2-mediated bacterial quorum sensing in Vibrio harveyi Yunfeng Cheng 1 , Nanting Ni 1 , Minyong Li 1 , Han-Ting Chou 2 , Chung-dar Lu 2 , Phang C Tai 2 , and Binghe Wang 1 . (1) Department of Chemistry, Georgia State University, 50 Decatur Street, Atlanta, GA 30303, jerry_cyf@hotmail.com, (2) Biology Center for Biotechnology and Drug Design, Georgia State University, Atlanta, GA 30303 Bacterial quorum sensing is a process of community-wide regulation of behaviors through the secretion and sensing of chemical autoinducers (AI). Because quorum sensing is implicated in pathologically relevant bacterial traits such as biofilm formation, conjugation, virulence factor production, and drug resistance, we are interested in developing quorum sensing inhibitors as potential therapeutic agents. In this effort, we conducted virtual screening against the audoinducer-2 (AI-2) receptor protein in Vibrio harveyi, LuxP. Among the 26 candidates selected for evaluation of their ability to inhibit AI-2 mediated quorum sensing, several showed good inhibitory activities in a bioluminescence assay (IC50: 40-50 micromolar). From these promising hits, 12 analogs were designed, synthesized, and evaluated. Several synthetic analogs showed improved activities. This presentation will discuss the design, synthesis, and structure-activity relationship studies of these AI-2 inhibitors.
MEDI 34 Pyrogallol and its analogs can antagonize bacterial quorum sensing in Vibrio harveyi Nanting Ni 1 , Gaurav Choudhary 2 , Minyong Li 1 , and Binghe Wang 1 . (1) Department of Chemistry, Georgia State University, 50 Decatur street, Atlanta, GA 30303, Fax: 404-413-5543, nni3@student.gsu.edu, (2) Department of Biology, Georgia State University, Atlanta, GA 30303 Bacteria can coordinate community-wide behaviors through quorum sensing, i.e., the secretion and sensing of autoinducer (AI) molecules. Bacterial quorum sensing is implicated in the regulation of pathologically relevant events such as biofilm formation, bacterial virulence and drug resistance. Inhibitors of bacterial quorum sensing could therefore be useful therapeutics. We are interested in finding quorum sensing antagonists by using Vibrio harveyi a model organism. We have found several catechol compounds capable of antagonizing AI-2-mediated pathway in V. harvey with pyrogallol having the lowest IC 50 at 2 µM. We postulate that the inhibitory effect of catechols was due to their ability to chelate boric acid the same way as DPD, the natural AI-2 molecule. It is interesting to note that these compounds also inhibit AI-1- mediated bacterial quorum sensing. Further studies are needed to fully understand their mechanisms of action. MEDI 35 Synthesis of selectively functionalized steroid-2á, 3â-diol stereoisomer Sunil K Upadhyay, Department of Chemistry, University of New Orleans, LA-70148, 102-CSB, 2000-lakeshore drive, New Orleans, LA 70148, supadhya@uno.edu, and Branco S. Jursic, Department of Chemistry, University of New Orleans, New Orleans, LA 70148 Natural sources for CAY-1 are laborious purification hampered further biological exploration of its antifungal activity and medical application. Hence there is demand for both structural simplification and preparation procedure for CAY-1 analogs as antifungal agents. Development of synthetic methodology for the preparation of mono OH-protected 2á, 3â-steroids, which are crucial building blocks for the preparation of potent antimicrobial therapeutic agents called saponins is of great importance. Previous studies shows that the 2á,3â-steroids part is essential part for good activity and the oligosaccharide part enhances solubility. We have developed highly efficient synthesis for mono protected-2á,3â-steroids isomer which in turn is very difficult as traditional methods will lead to the most favorable axial isomers due to steric reasons. Similar synthetic strategy was used for three different steroids from different sources to get the desired stereoisomer. We have developed amino acid based functionalization of steroids with same isomers to improve water solubility. Various steroids from different sources have been used to make the similar isomers to explore their biological activity.
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Page 3 and 4: discovery of S/GSK364735 was a resu
Page 5 and 6: compounds was then performed target
Page 7 and 8: MEDI 13 Potent, brain-penetrant, hy
Page 9 and 10: predominately in the liver, leads t
Page 11 and 12: Candidate Optimization Department,
Page 13 and 14: acceptor atoms as the core componen
Page 15 and 16: Prostaglandin (PG) D 2 is an allerg
Page 17: polymerization, as described, by pr
Page 21 and 22: Nicos A. Petasis 1 , Jasim Uddin 1
Page 23 and 24: Yong-Gil Kim, Joon Heo, Mi-Kyung Ji
Page 25 and 26: A new class of potent NK1 receptor
Page 27 and 28: The significant antiviral propertie
Page 29 and 30: Laboratories, West Point, PA 19486,
Page 31 and 32: MEDI 58 Preparation and antiviral a
Page 33 and 34: MEDI 62 Caco-2 cell based assay dev
Page 35 and 36: FMS-like tyrosine kinase 3 (FLT3) r
Page 37 and 38: MEDI 70 Synthesis of bisphosphonate
Page 39 and 40: ing. These observations suggest a p
Page 41 and 42: MEDI 77 Probing the structure-activ
Page 43 and 44: B-Raf kinase plays a critical role
Page 45 and 46: Gal-CS was used to prepare nanopart
Page 47 and 48: MEDI 88 Trifluoromethyl substituted
Page 49 and 50: MEDI 92 Discovery of novel small mo
Page 51 and 52: MEDI 96 Synthesis and antiprolifera
Page 53 and 54: MEDI 99 Development of novel antica
Page 55 and 56: MEDI 103 Discovery of N-aryl-9-oxo-
Page 57 and 58: Compounds that interfere with micro
Page 59 and 60: Carbonyl reductase (CR) has been im
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Page 63 and 64: MEDI 120 Novel purine based "atypic
Page 65 and 66: MEDI 124 Efficient removal of ruthe
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MEDI 131 Synthesis and biological e
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MEDI 135 Identification of AT-1002
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Spectroscopic evidence was used to
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MEDI 142 Molecular basis for irreve
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MEDI 146 Effect of fluorine on subs
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MEDI 151 Overview of newer approach
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MEDI 156 Defining structure-activit
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MEDI 160 Bivalent inhibitors of P-g
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MEDI 164 Molecular basis for effica
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MEDI 167 Discovery of the highly po
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highly asymmetric, closely packed d
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4/WP14-3, Sumneytown Pike, West Poi
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MEDI 179 Design, synthesis, and eva
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MEDI 182 Substituted-pyrrole 2-amin
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MEDI 186 Discovery and optimization
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phosphatase SHIP. Bioassay guided f
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epibatidine for nicotinic channels.
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derivative with striking solubility
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MEDI 203 Core-modified mannopeptimy
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MEDI 207 Enhancing the kinetic prof
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hydroxyphenyl)piperazin-1-yl)butyl)
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migration of people from these area
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Schistosomiasis is, after malaria,
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-Ketoacyl-ACP-synthase III (FabH) h
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MEDI 225 Synthesis of the analog of
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MEDI 229 Structure-based virtual sc
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MEDI 234 TG100801: A prodrug for th
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In the past, large collections of c
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approach to the treatment of autoim
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logPe values. The residual mean squ
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Oligo-chitosan (OCS) which is a kin
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characterization of novel muscarini
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MEDI 257 Rigid analogs of 4,4-diary
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MEDI 261 Strategies toward improvin
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disease. It is generally accepted t
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(BBB). Our preliminary in vitro dat
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It is well-documented that androgen
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MEDI 276 Investigating the manipula
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were screened by FACS sarin labeled
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MEDI 285 Design, synthesis and biol
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equipment set-up and large scale ma
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Significant effort has been directe
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esearch was supported by funds from
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synthesized a series of carbamoylch
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proceeded more rapidly by switching
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genes. With the understanding of th
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MEDI 310 Optimized methods for the
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Coupled with crystallographic data,
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MEDI 317 Design and synthesis of hy
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MEDI 320 Synthesis and antibacteria
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DTPA. Incorporation of the nitro fu
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MEDI 328 The mechanism of bioreduct
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esistance, there is an urgent need
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Giving the Rule-of-5 a more accurat
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MEDI 338 Structure guided design of
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MEDI 342 Synthesis of peptide-amilo
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MEDI 346 Design, synthesis, and ant
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