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Kinetics and mechanism of racemisation reactions of configurationally labile stereogenic centres in drug-like molecules in aqueous solutions; thiohydantoins and related compounds

Ahmad, Hiwa Omer 2015. Kinetics and mechanism of racemisation reactions of configurationally labile stereogenic centres in drug-like molecules in aqueous solutions; thiohydantoins and related compounds. PhD Thesis, Cardiff University.
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In this thesis, studies of the kinetic and mechanism of racemisation of several drug-like molecule have been presented. Chapter 1 provides background information on the general mechanisms of racemisation of drugs in general, and hydantoin derivatives. In particular including reviews of the hydrolysis and the mechanism of base-catalysed racemisation of hydantoin derivatives. The synthesis of different chiral hydantoins, thiohydantoins, thiazolidine-diones, and rhodanines is presented in Chapter 2. Several enantio-enriched 5-substituted 1-acetyl-2-thiohydantoins and two tri-substituted 2-thiohydantoins have been synthesised. Further racemic thiohydantoin derivatives including mono, di, and tri-substituted 2-thiohydantoins have also been prepared. Chapter 3 focuses on the kinetics and mechanism of hydrolysis of 5-substituted 1-acetyl-2-thiohydantoins in physiological-like buffers. The key reaction involves de-acetylation and this is followed by the hydrolysis of the resulting 5-substituted 2-thiohydantoins. Sodium hydroxide and hydrochloric acid have also been used for the hydrolysis of 1-acetyl-5-phenyl-2-thiohydantoin. Similarly, the hydrolysis of several 5-substituted 2-thiohydantoins has been studied. The rate constants for hydrolysis suggest that the 5-substituted 1-acetyl-2-thiohydantoins hydrolyses faster than the subsequent hydrolysis of 5-substituted 2-thiohydantoins. Chapter 4 focuses on the racemisation of 5-substituted 1-acetyl-2-thiohydantoins and shows that substituents at N-1 decelerate racemisation. Racemisation of tri-substituted 2-thiohydantoins is fast in comparison with 5-substituted 1-acetyl-2-thiohydantoins. The substituents at the asymmetric carbon affect the rate of racemisation. The solvent kinetic isotope effect on the racemisation were determined for different substituted 2-thiohydantoins and supported the SE1 mechanism of racemisation. Chapter 5 concerns further confirmation of the mechanism of racemisation by comparing kdeu and krac and this confirms the SE1 mechanism for racemisation of 5-substituted 1-acetyl-2-thiohydantoin as kdeu/krac for all compounds approaches 1. For the racemic 5-substituted 2-thiohydantoins the rate constants of deuteration have been obtained using 1H-NMR spectroscopy and showed fast replacement of hydrogen by deuteron. Assuming kdeu = krac, we can order the rate constants for racemisation form high to low as rhodanine > thiohydantoin > thiazolidine-2,4-dione > hydantoin.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Chemistry
Subjects: Q Science > QD Chemistry
Date of First Compliant Deposit: 30 March 2016
Last Modified: 28 Jun 2019 03:24

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