Alzheimer's disease (AD) is a progressive neurodegenerative disease, characterized by impairment of memory and cognitive abilities. Mitogen-activated protein kinase 14 (or p38α MAPK) and butyrylcholin esterase (BChE), represent targets, which play key roles in the onset and progression of this disease. In progression of AD, MAPK's signalling cascades demonstrate their role in processes of microglia and astrocyte-mediated neuroinflammation, in hyperphosphorylation of protein tau and in changes in alteration of synaptic plasticity in neurons. BChE, a serine hydrolase, catalyses the hydrolysis of acetylcholine, which has an important role in various cognitive processes and accumulates in amyloid plaques β and neurofibrillary tangles, where it stimulates their pathological activities.
In this Master's thesis, we synthesised and evaluated three potential dual azine BChE and p38α MAPK inhibitors. ARRY-371797, a known compound from Pfizer Inc. served us as the basis for synthesis of our compounds. In its structure, the 2,4-difluorophenoxy group, which we assumed interacts in the hydrophobic pocket of p38α MAPK's and acyl-binding pocket of BChE's binding site remained unchanged. -(CH2)2NMe2 functional group remained unchanged as well, since it includes -NMe2 functional group, which was important for the inhibitory potency of 1 through its cation-π interactions with Trp82 in the cholin-binding pocket of BChE’s binding site. When inhibiting p38α MAPK, we assumed that interaction between heterocyclic nitrogen and Met109 at the p38α MAPK's hinge region is also important. To preserve or even enhance inhibiting potency, we replaced the 1-isobuthyl-1H-indazole part with different azine rings, to obtain smaller and more flexible molecules. We also wanted to compare the influence of the position of nitrogen atoms on the inhibiting potency of inhibitors.
Residual activities of the synthesised compounds 16-18 did not show the desired potency. However, we still came to important conclusions. When binding to the binding site of p38α MAPK, large enough distance between nitrogen and 2,4-difluorophenoxy moiety is necessary. In that aspect, the most suitable core is heteroaromatic bicyclic core, for example indazole. When inhibiting BChE, instead of rigid azine structural core, some other core, with greater flexibility should be applied. This would enhance chances for the aforementioned interactions of other inhibitor’s fragments when binding to the binding site of BChE. In 1 for example, this core represents piperidine ring.
Compounds 16-18, despite their poor activity, still represent a good basis for further development and optimization of dual inhibitors of p38α MAPK and BChE for the treatment of AB.
|
