Abstrakt

Identification of the 3,4-dihydro-2h,6h-pyrimido[1,2-c][1,3]benzothiazine-6-imine derivatives as novel selective inhibitors of the Plasmodium falciparum dihydroorotate dehydrogenase

Endah Dwi Hartuti

Plasmodium falciparum is an apicomplexan parasite that is responsible for the development of malaria. Mitochondria carry out biochemical functions essential for almost all eukaryotic cells such as homeostasis calcium, signaling for cell death and survival also ATP production. In addition to that, mitochondria are also important organelle for de-novo pyrimidine biosynthesis. The inhibitor binding site of P. falciparum DHODH is known to be structurally divergent from the mammalian orthologue. The screening identified PD 404182 and its derivatives as rPfDHODH inhibitors and among them ten compounds showed IC50 of under 1 µM. The average Z`-factor was 0.875 ±0.088 and the coefficients of variation was 2.38% indicating excellent performance of the screening systems. Finally, PD 404182 and its derivative also inhibited the growth of P. falciparum 3D7, providing new starting points for antimalarial drug development.