Synthesis and pharmacological profile of new inhibitors of excitatory amino acid transporters and flow-based reaction optimisation in organic chemistry

Glutamate (Glu) is the main excitatory neurotransmitter in the mammalian CNS and mediates neurotransmission across most excitatory synapses. Under physiological conditions, the concentration of Glu in the synaptic cleft is kept at low level by excitatory amino acids transporters (EAATs). In some pathological conditions (e.g. ischemia), EAATs release additional Glu through a reversed mode of operation. Thus, EAAT blockers with low or no affinity for Glu receptors could be useful to prevent the Glu release and neuron death after cerebral ischemia. Since EAATs show stereoselective anomalies, in my PhD work I found it interesting to synthesise and test the single enantiomers of two model compounds, HIP-A, an analogue of aspartate, and HIP-B, which is structurally related to Glu. I designed derivatives which are structurally related to HIP-A and HIP-B and, through the evaluation of their activity at EAATs, it was possible to enucleate the pivotal pharmacophore components essential to confer the desired biological activity. I also synthesised new potential EAATs blockers with an aromatic group in position 4 of glutamic acid bound through an oxygen. In recent years, there has been considerable interest in substituted derivatives of thiazoles and imidazoles rings as antitumoral drugs. Using a modular flow reactor in combination to an immobilised base, I synthesised a small collection (35 compounds) of heterocycles, in overall yields of between 70 and 99% and in >95% purity.