1402938-41-3Relevant academic research and scientific papers
Identification of Phenylpyrazolone Dimers as a New Class of Anti-Trypanosoma cruzi Agents
Sijm, Maarten,Siciliano de Araújo, Julianna,Ramos Llorca, Alba,Orrling, Kristina,Stiny, Lydia,Matheeussen, An,Maes, Louis,de Esch, Iwan J. P.,de Nazaré Correia Soeiro, Maria,Sterk, Geert Jan,Leurs, Rob
, p. 1662 - 1668 (2019/08/30)
Chagas disease is becoming a worldwide problem; it is currently estimated that over six million people are infected. The two drugs in current use, benznidazole and nifurtimox, require long treatment regimens, show limited efficacy in the chronic phase of infection, and are known to cause adverse effects. Phenotypic screening of an in-house library led to the identification of 2,2′-methylenebis(5-(4-bromophenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one), a phenyldihydropyrazolone dimer, which shows an in vitro pIC50 value of 5.4 against Trypanosoma cruzi. Initial optimization was done by varying substituents of the phenyl ring, after which attempts were made to replace the phenyl ring. Finally, the linker between the dimer units was varied, ultimately leading to 2,2′-methylenebis(5-(3-bromo-4-methoxyphenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (NPD-0228) as the most potent analogue. NPD-0228 has an in vitro pIC50 value of 6.4 against intracellular amastigotes of T. cruzi and no apparent toxicity against the human MRC-5 cell line and murine cardiac cells.
Catechol pyrazolinones as trypanocidals: Fragment-based design, synthesis, and pharmacological evaluation of nanomolar inhibitors of trypanosomal phosphodiesterase B1
Orrling, Kristina M.,Jansen, Chimed,Vu, Xuan Lan,Balmer, Vreni,Bregy, Patrick,Shanmugham, Anitha,England, Paul,Bailey, David,Cos, Paul,Maes, Louis,Adams, Emily,Van Den Bogaart, Erika,Chatelain, Eric,Ioset, Jean-Robert,Van De Stolpe, Andrea,Zorg, Stèphanie,Veerman, Johan,Seebeck, Thomas,Sterk, Geert Jan,De Esch, Iwan J. P.,Leurs, Rob
, p. 8745 - 8756 (2013/01/15)
Trypanosomal phosphodiesterases B1 and B2 (TbrPDEB1 and TbrPDEB2) play an important role in the life cycle of Trypanosoma brucei, the causative parasite of human African trypanosomiasis (HAT), also known as African sleeping sickness. We used homology modeling and docking studies to guide fragment growing into the parasite-specific P-pocket in the enzyme binding site. The resulting catechol pyrazolinones act as potent TbrPDEB1 inhibitors with IC50 values down to 49 nM. The compounds also block parasite proliferation (e.g., VUF13525 (20b): T. brucei rhodesiense IC50 = 60 nM, T. brucei brucei IC50 = 520 nM, T. cruzi = 7.6 μM), inducing a typical multiple nuclei and kinetoplast phenotype without being generally cytotoxic. The mode of action of 20b was investigated with recombinantly engineered trypanosomes expressing a cAMP-sensitive FRET sensor, confirming a dose-response related increase of intracellular cAMP levels in trypanosomes. Our findings further validate the TbrPDEB family as antitrypanosomal target.
