Malaria, caused by parasites of the genus Plasmodium, is responsible for over 600'000 deaths per year.1? Emerging resistances against malaria drugs demand for the development of new antimalarials.Humans utilize the mevalonate pathway for the biosynthesis of isoprenoids, whereas many pathogens, such as P. falciparum exclusively obtain isoprenoids via the non-mevalonate pathway, which is a validated target for treatment of malaria.2In this pathway, the enzyme IspF catalyzes the cyclization of diphosphocytidyl-2-methylerythritol 2-phosphate into 2-methylerythritol 2,4-cyclodiphosphate. The IspF enzyme is active as a trimer with three active sites.The inhibition of plant IspF enzyme from A. thaliana was screened against 40'000 compounds. A bis-sulfonamide derivative was identified as possible inhibitor. Several derivatives were synthesized, the most active showing one-digit micromolar IC50 values against P. falciparum IspF.The dissociation constant of the most active bissulfonamide to the three active sites was determined by ESI-MS.1 World Health Organisation, �World Malaria Report 2013�, Geneva, 2009. 2 M. A. Missinou, S. Borrmann, A. Schindler, S. Issifou, A. A. Adegnika, P. B. Matsiegui, R. Binder, B. Lell, J. Wiesner, T. Baranek, H. Jomaa, P. G. Kremsner, Lancet 2002  , 360, 1941�1942.

Bis-sulfonamide inhibitors of 2-methylerythritol 2,4-cyclodiphosphate synthase (IspF) from <i>Arabidopsis thaliana</i> and <i>Plasmodium falciparum</i>

248th National Meeting (2014)

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Bis-sulfonamide inhibitors of 2-methylerythritol 2,4-cyclodiphosphate synthase (IspF) from Arabidopsis thaliana and Plasmodium falciparum