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Synthesis and development of small molecule inhibitors targeting viral PAn endonuclease and bacterial MreB
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Sawant, Rajlakshmi. Synthesis and development of small molecule inhibitors targeting viral PAn endonuclease and bacterial MreB. Retrieved from https://doi.org/doi:10.7282/T35M694N

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TitleSynthesis and development of small molecule inhibitors targeting viral PAn endonuclease and bacterial MreB
NameSawant, Rajlakshmi (author); LaVoie, Edmond J (chair); Hu, Longqin (internal member); Rice, Joseph E (internal member); Rutgers University; School of Graduate Studies
Date Created2018
Other Date2018-05 (degree)
SubjectMedicinal Chemistry, Influenza A virus, Antiviral agents
Extent1 online resource (xi, 83 p. : ill.)
DescriptionImminent 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.
NoteM.S.
NoteIncludes bibliographical references
Noteby Rajlakshmi Sawant
Genretheses, ETD graduate
Persistent URLhttps://doi.org/doi:10.7282/T35M694N
Languageeng
CollectionSchool of Graduate Studies Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.
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