Malaria is still a major global health challenge as current drug therapies are compromised by resistance. Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) was validated as a new drug target after triazolopyrimidine-based inhibitors showed anti-malarial activity in vivo[1,2]. Here, we firstly present the synthesis and the biologically evaluation of a new series of PfDHODH inhibitors bearing 3-hydroxypyrazole moiety (compounds 1 - 4). Compound 1 showed a micromolar activity on PfDHODH while it is inactive against the human DHODH isoform. This prelinary result suggests that 1 could represent an interesting lead compound for design new selective PfDHODH inhibitors. When docked inside the PfDHODH binding pocket, the carboxylic function present in 1, ionized at physiological pH, seems to play a fondamental role. We hypothize that it could interact with protonated Arg 265, a key aminoacid present in the pocket where inhibitors explain their activity. Additional lipophilic pockets are present close to the Arg 265 residue, one of them could be easily occupied by the phenoxy moiety of 1 (figure 1). These assumptions allowed us to design new derivatives based on the 1H-4-carboxypyrazole scaffold that could present additional interactions with the protein. The biological assay of this second series would confirm whether our ligand-protein interaction assumptions are correct and will allow us to explore the binding site of PfDHODH, searching for more potent and selective inhibitors based on 1H-4-carboxypyrazole scaffold. In the second group of compounds the presence of substitutuents on the hydroxyl and phenoxyl moieties of 1 (see structures c, figure 1) was investigated, together with the the heteroatom substitution in the phenoxyl scaffold. Synthesis and pharmacological profiling of this second modulation are presented and fully discussed.
1H-pyrazole-4-carboxylic acids active against Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH): discovery of a new scaffold for development of antimalarial agents
PIPPIONE, Agnese Chiara;BOSCHI, Donatella;LOLLI, Marco Lucio
2014-01-01
Abstract
Malaria is still a major global health challenge as current drug therapies are compromised by resistance. Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) was validated as a new drug target after triazolopyrimidine-based inhibitors showed anti-malarial activity in vivo[1,2]. Here, we firstly present the synthesis and the biologically evaluation of a new series of PfDHODH inhibitors bearing 3-hydroxypyrazole moiety (compounds 1 - 4). Compound 1 showed a micromolar activity on PfDHODH while it is inactive against the human DHODH isoform. This prelinary result suggests that 1 could represent an interesting lead compound for design new selective PfDHODH inhibitors. When docked inside the PfDHODH binding pocket, the carboxylic function present in 1, ionized at physiological pH, seems to play a fondamental role. We hypothize that it could interact with protonated Arg 265, a key aminoacid present in the pocket where inhibitors explain their activity. Additional lipophilic pockets are present close to the Arg 265 residue, one of them could be easily occupied by the phenoxy moiety of 1 (figure 1). These assumptions allowed us to design new derivatives based on the 1H-4-carboxypyrazole scaffold that could present additional interactions with the protein. The biological assay of this second series would confirm whether our ligand-protein interaction assumptions are correct and will allow us to explore the binding site of PfDHODH, searching for more potent and selective inhibitors based on 1H-4-carboxypyrazole scaffold. In the second group of compounds the presence of substitutuents on the hydroxyl and phenoxyl moieties of 1 (see structures c, figure 1) was investigated, together with the the heteroatom substitution in the phenoxyl scaffold. Synthesis and pharmacological profiling of this second modulation are presented and fully discussed.
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
