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Synthesis and development of small molecule inhibitors targeting viral PAn endonuclease and bacterial MreB

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TitleInfo
Title
Synthesis and development of small molecule inhibitors targeting viral PAn endonuclease and bacterial MreB
Name (type = personal)
NamePart (type = family)
Sawant
NamePart (type = given)
Rajlakshmi
NamePart (type = date)
1992-
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Rajlakshmi Sawant
Role
RoleTerm (authority = RULIB)
author
Name (type = personal)
NamePart (type = family)
LaVoie
NamePart (type = given)
Edmond J
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Edmond J LaVoie
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Advisory Committee
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RoleTerm (authority = RULIB)
chair
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NamePart (type = family)
Hu
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Longqin
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Longqin Hu
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Advisory Committee
Role
RoleTerm (authority = RULIB)
internal member
Name (type = personal)
NamePart (type = family)
Rice
NamePart (type = given)
Joseph E
DisplayForm
Joseph E Rice
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
internal member
Name (type = corporate)
NamePart
Rutgers University
Role
RoleTerm (authority = RULIB)
degree grantor
Name (type = corporate)
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School of Graduate Studies
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school
TypeOfResource
Text
Genre (authority = marcgt)
theses
OriginInfo
DateCreated (qualifier = exact)
2018
DateOther (qualifier = exact); (type = degree)
2018-05
CopyrightDate (encoding = w3cdtf); (qualifier = exact)
2018
Place
PlaceTerm (type = code)
xx
Language
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eng
Abstract (type = abstract)
Imminent threat of pandemics of influenza, along with increasing resistance of the virus to existing anti-viral drugs has posed a need for development of an anti-viral that possesses a novel mechanism of action. PAN Endonuclease enzyme protein plays an important role in influenza A viral transcription with the cap-snatching process being highly conserved in the virus. This makes PAN an attractive target for drug development. Our efforts began with fragment screening to identify an effective pharmacophore. 5-chloro-3-hydroxypyridin-2(1H)-one was identified as a highly active chelating ligand at the endonuclease site containing metal ions. After extensive research, 3-hydroxypyridin-2(1H)-ones, 3-hydroxyquinolin-2(1H)-ones and aza analogs of 3-hydroxypyridin-2(1H)-ones were prepared which displayed modest enzymatic inhibitory activity. This activity didn’t translate in the cellular assay. Hence, we synthesized a known endonuclease inhibitor (Shionogi Co.) to check whether the established structure activity relationships were “false-positive” data. We also experimented with the development of isatin derivatives to continue the search for a lead compound. The most promising compound, 6-Bromo-1-hydroxyindoline-2,3-dione showed 45% inhibition at 200 μM concentration. This molecule was optimized to give 6-(4-fluorophenyl)-1,3-dihydroxy-3-methylindolin-2-one which showed no inhibitory activity in the enzyme assay. Despite of unsuccessful attempts, continued efforts are being made to explore PAN as a potential target for antiviral therapy. Our research efforts were then directed towards tackling another emerging global health crisis, the antibiotic resistance crisis. With increasing bacterial strains developing resistance towards currently available antibiotics, there is a need to target a novel mechanism of action in bacteria. MreB, a highly conserved actin homologue in bacteria is important in cell wall synthesis and determining the cell shape in bacteria. The significance of MreB in bacterial cell growth makes it a lucrative target for design of antibiotics. A22 was identified as an MreB inhibitor with modest inhibitory activity. Our efforts were focused on studying the structure activity relationships by modifying the aromatic core of A22. A series of benzothiophene, benzofuran and indole based isothioureas was synthesized. Deductions made from SAR studies are currently being used to develop an optimized lead that can show substantial MreB inhibitory activity and can further be developed into clinic.
Subject (authority = RUETD)
Topic
Medicinal Chemistry
RelatedItem (type = host)
TitleInfo
Title
Rutgers University Electronic Theses and Dissertations
Identifier (type = RULIB)
ETD
Identifier
ETD_8792
PhysicalDescription
Form (authority = gmd)
electronic resource
InternetMediaType
application/pdf
InternetMediaType
text/xml
Extent
1 online resource (xi, 83 p. : ill.)
Note (type = degree)
M.S.
Note (type = bibliography)
Includes bibliographical references
Subject (authority = ETD-LCSH)
Topic
Influenza A virus
Subject (authority = ETD-LCSH)
Topic
Antiviral agents
Note (type = statement of responsibility)
by Rajlakshmi Sawant
RelatedItem (type = host)
TitleInfo
Title
School of Graduate Studies Electronic Theses and Dissertations
Identifier (type = local)
rucore10001600001
Location
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NjNbRU
Identifier (type = doi)
doi:10.7282/T35M694N
Genre (authority = ExL-Esploro)
ETD graduate
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RightsDeclaration (ID = rulibRdec0006)
The author owns the copyright to this work.
RightsHolder (type = personal)
Name
FamilyName
Sawant
GivenName
Rajlakshmi
Role
Copyright Holder
RightsEvent
Type
Permission or license
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2018-04-09 17:39:36
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Name
Rajlakshmi Sawant
Role
Copyright holder
Affiliation
Rutgers University. School of Graduate Studies
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Type
License
Name
Author Agreement License
Detail
I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
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