Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 1662-1668 |
| Number of pages | 7 |
| Journal | ChemMedChem |
| Volume | 14 |
| Issue number | 18 |
| DOIs | |
| Publication status | Published - 1 Jan 2019 |
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Keywords
- benznidazole
- Chagas disease
- nifurtimox
- phenotypic screening
- Trypanosoma cruzi
Cite this
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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.
In: ChemMedChem, Vol. 14, No. 18, 01.01.2019, p. 1662-1668.Research output: Contribution to Journal › Article › Academic › peer-review
TY - JOUR
T1 - Identification of Phenylpyrazolone Dimers as a New Class of Anti-Trypanosoma cruzi Agents
AU - Sijm, Maarten
AU - Siciliano de Araújo, Julianna
AU - Ramos Llorca, Alba
AU - Orrling, Kristina
AU - Stiny, Lydia
AU - Matheeussen, An
AU - Maes, Louis
AU - de Esch, Iwan J.P.
AU - de Nazaré Correia Soeiro, Maria
AU - Sterk, Geert Jan
AU - Leurs, Rob
PY - 2019/1/1
Y1 - 2019/1/1
N2 - 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.
AB - 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.
KW - benznidazole
KW - Chagas disease
KW - nifurtimox
KW - phenotypic screening
KW - Trypanosoma cruzi
UR - http://www.scopus.com/inward/record.url?scp=85071317667&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85071317667&partnerID=8YFLogxK
U2 - 10.1002/cmdc.201900370
DO - 10.1002/cmdc.201900370
M3 - Article
VL - 14
SP - 1662
EP - 1668
JO - ChemMedChem
JF - ChemMedChem
SN - 1860-7179
IS - 18
ER -