Controlled Access. Restriction lift date: 2035-05-31
Synthesis of novel IMPDH inhibitors
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Date
2024
Authors
Upadhyay, Amit
Journal Title
Journal ISSN
Volume Title
Publisher
University College Cork
Published Version
Abstract
Inosine-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.
Description
Controlled Access
Keywords
Nucleotide metabolism , IMPDH inhibitors , Antibacterial , Heteroaryls , Synthesis
Citation
Upadhyay, A. 2024. Synthesis of novel IMPDH inhibitors. PhD Thesis, University College Cork.