Malaria is estimated to have caused 584,000 deaths and 198 million cases of the disease globally in 2013. Four strains of Plasmodium parasite cause malaria in humans and the disease is transferred by Anopheles mosquitos. Though mortality rates are down 47% globally since 2000 and significant progress has been made in the quest for eradication, reported occurrences of resistance against current therapeutics threatens to reverse that progress. Longstanding treatment chloroquine has seen resistance since the 1950’s, with resistance becoming widespread in the 70’s and 80’s. In order to curb further resistance, it is essential that new antimalarial compounds be brought through the pipeline. To further our efforts on antimalarial 4(1H)-quinolones, we have turned to 4(1H)-quinolone ICI 56,780, an antimalarial with significant potency, yet sub-par properties and bioavailability. By completing a full structure-activity and structure-property relationship study on ICI 56,780, focusing on the improvement of aqueous solubility and microsomal stability, we have ultimately revealed several frontrunner compounds with superb in vivo antimalarial activity. The best compounds were found to be curative with all mice surviving a Plasmodium berghei infection after 30 days. Furthermore, frontrunner compounds were also shown to be mitochondrial inhibitors acting against all life cycle stages of P. falciparum. The new discoveries are significant as mitochondrial inhibitors have the potential to advance the malaria elimination campaign by blocking parasite development in the blood and liver, as well as preventing transmission to mosquitoes.

Optimization of 4(1H)-quinolone antimalarials for oral bioavailability and in vivo efficacy

253rd National Meeting (2017)

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