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