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Hydroxyazole scaffold-based Plasmodium falciparum dihydroorotate dehydrogenase inhibitors : Synthesis, biological evaluation and X-ray structural studies

Pippione, Agnese C.; Sainas, Stefano; Goyal, Parveen; Fritzson, Ingela LU ; Cassiano, Gustavo C.; Giraudo, Alessandro; Giorgis, Marta; Tavella, Tatyana A.; Bagnati, Renzo and Rolando, Barbara, et al. (2019) In European Journal of Medicinal Chemistry 163. p.266-280
Abstract

Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) has been clinically validated as a target for antimalarial drug discovery, as a triazolopyrimidine class inhibitor (DSM265) is currently undergoing clinical development. Here, we have identified new hydroxyazole scaffold-based PfDHODH inhibitors belonging to two different chemical series. The first series was designed by a scaffold hopping strategy that exploits the use of hydroxylated azoles. Within this series, the hydroxythiadiazole 3 was identified as the best selective PfDHODH inhibitor (IC50 12.0 μM). The second series was designed by modulating four different positions of the hydroxypyrazole scaffold. In particular, hydroxypyrazoles 7e and 7f were shown to be... (More)

Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) has been clinically validated as a target for antimalarial drug discovery, as a triazolopyrimidine class inhibitor (DSM265) is currently undergoing clinical development. Here, we have identified new hydroxyazole scaffold-based PfDHODH inhibitors belonging to two different chemical series. The first series was designed by a scaffold hopping strategy that exploits the use of hydroxylated azoles. Within this series, the hydroxythiadiazole 3 was identified as the best selective PfDHODH inhibitor (IC50 12.0 μM). The second series was designed by modulating four different positions of the hydroxypyrazole scaffold. In particular, hydroxypyrazoles 7e and 7f were shown to be active in the low μM range (IC50 2.8 and 5.3 μM, respectively). All three compounds, 3, 7e and 7f showed clear selectivity over human DHODH (IC50 > 200 μM), low cytotoxicity, and retained micromolar activity in P. falciparum-infected erythrocytes. The crystallographic structures of PfDHODH in complex with compounds 3 and 7e proved their binding mode, supplying essential data for future optimization of these scaffolds.

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keywords
Bioisosterism, Dihydroorotate dehydrogenase (DHODH) inhibitors, Malaria, Plasmodium falciparum, Pyrazole, Scaffold hopping, X-ray-crystallography
in
European Journal of Medicinal Chemistry
volume
163
pages
15 pages
publisher
Elsevier Masson SAS
external identifiers
  • scopus:85057887409
ISSN
0223-5234
DOI
10.1016/j.ejmech.2018.11.044
language
English
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yes
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3ef1f8ee-7c89-4c52-b7f0-d9a89b946016
date added to LUP
2018-12-17 14:46:09
date last changed
2019-02-20 11:40:06
@article{3ef1f8ee-7c89-4c52-b7f0-d9a89b946016,
  abstract     = {<p>Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) has been clinically validated as a target for antimalarial drug discovery, as a triazolopyrimidine class inhibitor (DSM265) is currently undergoing clinical development. Here, we have identified new hydroxyazole scaffold-based PfDHODH inhibitors belonging to two different chemical series. The first series was designed by a scaffold hopping strategy that exploits the use of hydroxylated azoles. Within this series, the hydroxythiadiazole 3 was identified as the best selective PfDHODH inhibitor (IC<sub>50</sub> 12.0 μM). The second series was designed by modulating four different positions of the hydroxypyrazole scaffold. In particular, hydroxypyrazoles 7e and 7f were shown to be active in the low μM range (IC<sub>50</sub> 2.8 and 5.3 μM, respectively). All three compounds, 3, 7e and 7f showed clear selectivity over human DHODH (IC<sub>50</sub> &gt; 200 μM), low cytotoxicity, and retained micromolar activity in P. falciparum-infected erythrocytes. The crystallographic structures of PfDHODH in complex with compounds 3 and 7e proved their binding mode, supplying essential data for future optimization of these scaffolds.</p>},
  author       = {Pippione, Agnese C. and Sainas, Stefano and Goyal, Parveen and Fritzson, Ingela and Cassiano, Gustavo C. and Giraudo, Alessandro and Giorgis, Marta and Tavella, Tatyana A. and Bagnati, Renzo and Rolando, Barbara and Caing-Carlsson, Rhawnie and Costa, Fabio T.M. and Andrade, Carolina Horta and Al-Karadaghi, Salam and Boschi, Donatella and Friemann, Rosmarie and Lolli, Marco L.},
  issn         = {0223-5234},
  keyword      = {Bioisosterism,Dihydroorotate dehydrogenase (DHODH) inhibitors,Malaria,Plasmodium falciparum,Pyrazole,Scaffold hopping,X-ray-crystallography},
  language     = {eng},
  pages        = {266--280},
  publisher    = {Elsevier Masson SAS},
  series       = {European Journal of Medicinal Chemistry},
  title        = {Hydroxyazole scaffold-based Plasmodium falciparum dihydroorotate dehydrogenase inhibitors : Synthesis, biological evaluation and X-ray structural studies},
  url          = {http://dx.doi.org/10.1016/j.ejmech.2018.11.044},
  volume       = {163},
  year         = {2019},
}