Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive memory loss and deterioration of cognitive functions. The main pathological features of the disease are amyloid-β (Aβ) plaques and neurofibrillary tangles. In addition, inflammation of the central nervous system (neuroinflammation) also plays a crucial role. The first sign of neuroinflammation is microglial activation, with the pro-inflammatory M1 phenotype releasing cytokines that activate the formation of NLRP3 inflammasome. Following NLRP3 inflammasome activation, proinflammatory cysteine caspase-1 is activated via prodomain removal and cleaves pro-IL-1β into its active form IL-1β. In mouse models of AD, pharmacological inhibition of caspase-1 prevented progressive accumulation of Aβ plaques, reduced neuroinflammation, and maintained normal concentrations of synaptophysin in the hippocampus.
Screening of the electrophilic fragment library assembled at UL FFA identified three covalent warhead fragment hits - carbamoyl fluoride, 1,3,4-oxathiazol-2-one, and imidazolide - that inhibited the enzymatic activity of caspase-1. In this master's thesis, we synthesised analogues of two hits –1,3,4-oxathiazol-2-one B and carbamoyl fluoride C – by changing the substituents on the basic scaffold (substituents on indoline in the analogues of hit C) or by replacing the phenyl ring with furan and its analogues (hit B). In addition, the carbamoyl fluoride warhead on indoline was replaced by other known electrophilic groups from literature. After establishing and optimising the synthetic pathway, we prepared 23 compounds for which we determined the inhibitory potencies against human caspase-1. Caspase-1 was inhibited by eight carbamoyl fluorides, while the remaining fragments were inactive. The results suggest that inhibitory activity is favoured by the presence of sterically small substituents (e.g., fluorine, nitro or hydroxy) at positions 5 or 6 of indoline, whereas acetate esters at position 3 are also tolerated. The latter also provide the best starting point for optimisation of inhibitory activity and further fragment growth.
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