Candidate drugs related to the lead compound propafenone are highly effective inhibitors of P. falciparum growth with 50% inhibitory concentrations (IC50s) in the sub-micromolar range. The parental compound propafenone is a cardiac sodium channel blocker which is in clinical use for the treatment of ventricular arrhythmia. An in house library of more than 400 compounds with systematically varied structures is available for 2D and 3D quantitative structure activity relationship studies. In a first step selected compounds were evaluated for their antimalarial activity using the histidine-rich protein 2 drug sensitivity assay. Propafenone analogues contain an inherently photoactive aryl-carbonyl substructure, which allows their use in photolabeling studies. Labelling efficiency is increased for compounds in which the phenylpropiophenone core structure is replaced by a benzophenone substructure. However, the phenylpropiophenone substructure represents part of the pharmacophore of the compounds. Benzophenone-type analogues show IC 50 values that are higher than their congeneric phenylpropiophenones. Nevertheless, one of the photoligands shows an IC50 value in the low micro-molar range. Use of this photoligand is thus expected to allow identification of candidate targets by mass spectrometry following two dimensional separation of the plasmodial proteome. The Malaria Genome Project has advanced our understanding of parasite biology and development of novel drugs can mount on data made available by the recently completed sequencing effort of P. falciparum. The lead compound propafenone is a registered drug and this compound class might therefore have a major potential as an antimalarial drug, either alone, or in combination with conventional antimalarials.