Synthesis and biological evaluation of three novel antimalarial series

• Main Author: Tunstall, Lucy Victoria
• Published: Keele University 2018
• Subjects: Q Science (General)
• Online Access: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.754782

This research explored the optimisation of three novel antimalarial series based on the MMV compound leads shown below. Extensive research began to optimise these potent hits through exploration of multiple functional group substitutions on two or more sites of the core structure (shown above). The highest activity tetrahydro-β-carboline analogue discovered during this research was LVT30 (IC50=1μM) which possesses an absent C3 interaction and a p-trifluoromethyl R2 substitution. Meanwhile, of the spirocyclic subset of derivatives, a high nanomolar activity compound was generated LVT86 (IC50=960 nM), possessing a butyl R1 chain and a m-trifluoromethyl R2 group and future work will include optimisation of this analogues pharmacokinetic properties. The most fruitful subseries of this project was a catalogue of 2-iminobenzimidazole compounds. In an attempt to optimise activity and increase potency, exploration involved variation of all three R positions and as a result, generated the most potent derivative over all three series. Compound LVTa95 possesses an inhibitory concentration of 33.4 nM and exhibits: a pentane R1 group, 2,4-dichloro R2 substitution and a hydroxy R3 group. As this compound existed as enantiomers, they were subsequently separated, and it was found both stereoisomers had similar activity.