Synthesis of MCR-1 inhibitors to overcome antibacterial resistance
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This thesis describes the synthesis of a series of pyrazole and isoflavone analogues in order to find drug-like molecules which can act as an inhibitor of MCR-1 (mobilised colistin resistance). This enzyme causes resistance to the last resort antibiotic - colistin (polymyxin E) which has recently become a global concern due to its easily transmissible nature. Two types of pyrazole analogues were prepared – disubstituted and trisubstituted pyrazole rings. For the synthesis of trisubstituted pyrazole analogues – a sequence involving a Friedel-Crafts acylation, a Kostanecki acylation and an aza-Michael addition was followed to form an alkyldiarylpyrazole ring. On the other hand, for the disubstituted pyrazoles – a sequence involving Suzuki coupling of an iodochromone and a boronic acid was used followed by an aza-Michael addition. After the initial synthesis of two pyrazole analogues, testing of these compounds was performed using NMR techniques to examine the binding of these compounds with the MCR-1 protein. The results from these initial studies were positive and demonstrated that there was binding towards MCR-1 but the low solubility of several compounds was noted and became a major concern at that time. Analogues with a greater number of hydroxyl groups were, therefore, prepared to increase the water solubility. However, the higher number of hydroxyl groups present in the starting materials resulting in the formation of complex mixtures during the reaction sequence, causing difficult separations and low yields. At that point, following a discussion of potential side products, a transesterification step was introduced into the synthetic sequence, which managed to dramatically minimise the number of side products formed and greatly increased the yields achieved. In total, 10 pyrazoles and 11 isoflavones were synthesised and 7 pyrazoles and 5 isoflavones have been tested together with colistin against E. coli with mcr-1 resistance. Initial results are very positive, with 6 out of the 13 compounds tested found to decrease the minimum inhibitory concentration (MIC) of polymyxin towards E. coli with mcr-1 resistance. This research is ongoing, and we are currently synthesising more structural analogues, guided by the biological results as they are released. In the future, the aim is to be able to build a picture of the structure-activity-relationship required for MCR-1 inhibition.