Synthesis of novel IMPDH inhibitors

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dc.check.date2035-05-31
dc.check.infoControlled Access
dc.contributor.advisorO'Sullivan, Tim
dc.contributor.authorUpadhyay, Amiten
dc.contributor.funderIrish Research Councilen
dc.contributor.funderHigher Education Authorityen
dc.date.accessioned2025-02-07T15:54:08Z
dc.date.available2025-02-07T15:54:08Z
dc.date.issued2024en
dc.date.submitted2024
dc.descriptionControlled Access
dc.description.abstractInosine-5’-monophosphate dehydrogenase (IMPDH) is an important enzyme involved in the biosynthesis of guanine nucleotides. The use of IMPDH as a target for developing novel antimicrobial agents forms the basis of this research. Chapter 1 provides an overview of recently developed antimicrobial IMPDH inhibitors from the literature. The background to this project and the main aims and objectives are also outlined. Chapter 2 describes the development of synthetic routes to two related compound libraries. The first series comprises benzyl-containing urea analogues, while the second series all contain a common 3-nitro-4-chlorophenyl ring. The introduction of several heteroaryl/aryl rings via Suzuki- Miyaura coupling is also described. The synthesis of a third group of compounds incorporating a squaramide bioisostere in place of the urea group is discussed in Chapter 3. In silico analysis of all compounds is described in Chapter 4. Important ADME properties (e.g. LogP, TPSA, pKa) are calculated to determine the suitability of these compounds for future development. This chapter also details the screening of several compounds for activity against P. aeruginosa IMPDH, with a number of molecules displaying sub-micromolar activity. Additionally, biological evaluation of three potent candidates against S. aureus IMPDH and E. coli IMPDH is included in this chapter. A docking study of both synthesised and virtual inhibitors using the CpIMPDH enzyme as the target is contained in Chapter 5. Chapter 6 details the main conclusions of this work and proposes several avenues for future investigation. Chapter 7 contains all relevant experimental procedures, including spectroscopic and analytical data.en
dc.description.statusNot peer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationUpadhyay, A. 2024. Synthesis of novel IMPDH inhibitors. PhD Thesis, University College Cork.
dc.identifier.endpage290
dc.identifier.urihttps://hdl.handle.net/10468/17009
dc.language.isoenen
dc.publisherUniversity College Corken
dc.relation.projectIrish Research Council (Grant no. GOIPG/2019/1117)
dc.relation.projectHigher Education Authority (4760/R20504)
dc.rights© 2024, Amit Upadhyay.
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectNucleotide metabolism
dc.subjectIMPDH inhibitors
dc.subjectAntibacterial
dc.subjectHeteroaryls
dc.subjectSynthesis
dc.titleSynthesis of novel IMPDH inhibitorsen
dc.typeDoctoral thesisen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD - Doctor of Philosophyen
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