Novel inhibitors of Plasmodium falciparum based on 2,5-disubstituted furans

Phenotypic HTS campaigns with a blood stage malaria assay have been used to discover novel chemotypes for malaria treatment with potential alternative mechanisms of action compared to existing agents. N¹-(5-(3-Chloro-4-fluorophenyl)furan-2-yl)-N³,N³-dimethylpropane-1,3-diamine, 1 was identified as a modest inhibitor of P. falciparum NF54 (IC₅₀ = 875 nM) with an apparent long plasma half-life after high dose oral administration to mice, although the compound later showed poor metabolic stability in liver microsomes through ring- and side chain-oxidation and N-dealkylation. We describe here the synthesis of derivatives of 1, exploring the influence of substitution patterns around the aromatic ring, variations on the alkyl chain and modifications in the core heterocycle, in order to probe potency and metabolic stability, where 4k showed a long half-life in rats.