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Design, synthesis, biological evaluation and X-ray structural studies of potent human dihydroorotate dehydrogenase inhibitors based on hydroxylated azole scaffolds

Sainas, Stefano; Pippione, Agnese C.; Giorgis, Marta; Lupino, Elisa; Goyal, Parveen; Ramondetti, Cristina; Buccinnà, Barbara; Piccinini, Marco; Braga, Rodolpho C. and Andrade, Carolina H., et al. (2017) In European Journal of Medicinal Chemistry 129. p.287-302
Abstract

A new generation of potent hDHODH inhibitors designed by a scaffold-hopping replacement of the quinolinecarboxylate moiety of brequinar, one of the most potent known hDHODH inhibitors, is presented here. Their general structure is characterized by a biphenyl moiety joined through an amide bridge with an acidic hydroxyazole scaffold (hydroxylated thiadiazole, pyrazole and triazole). Molecular modelling suggested that these structures should adopt a brequinar-like binding mode involving interactions with subsites 1, 2 and 4 of the hDHODH binding site. Initially, the inhibitory activity of the compounds was studied on recombinant hDHODH. The most potent compound of the series in the enzymatic assays was the thiadiazole analogue 4... (More)

A new generation of potent hDHODH inhibitors designed by a scaffold-hopping replacement of the quinolinecarboxylate moiety of brequinar, one of the most potent known hDHODH inhibitors, is presented here. Their general structure is characterized by a biphenyl moiety joined through an amide bridge with an acidic hydroxyazole scaffold (hydroxylated thiadiazole, pyrazole and triazole). Molecular modelling suggested that these structures should adopt a brequinar-like binding mode involving interactions with subsites 1, 2 and 4 of the hDHODH binding site. Initially, the inhibitory activity of the compounds was studied on recombinant hDHODH. The most potent compound of the series in the enzymatic assays was the thiadiazole analogue 4 (IC5016 nM). The activity was found to be dependent on the fluoro substitution pattern at the biphenyl moiety as well as on the choice/substitution of the heterocyclic ring. Structure determination of hDHODH co-crystallized with one representative compound from each series (4, 5 and 6) confirmed the brequinar-like binding mode as suggested by modelling. The specificity of the observed effects of the compound series was tested in cell-based assays for antiproliferation activity using Jurkat cells and PHA-stimulated PBMC. These tests were also verified by addition of exogenous uridine to the culture medium. In particular, the triazole analogue 6 (IC50against hDHODH: 45 nM) exerted potent in vitro antiproliferative and immunosuppressive activity without affecting cell survival.

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keywords
Autoimmune diseases, Bioisosterism, Brequinar, Dihydroorotate dehydrogenase (DHODH) inhibitors, Leflunomide, X-ray-crystallography
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European Journal of Medicinal Chemistry
volume
129
pages
16 pages
publisher
Elsevier Masson SAS
external identifiers
  • scopus:85013477696
  • wos:000397180800019
ISSN
0223-5234
DOI
10.1016/j.ejmech.2017.02.017
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English
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yes
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1ac0c427-5282-4228-b062-02cb90801f1f
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2017-03-09 08:51:36
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2017-09-18 11:38:16
@article{1ac0c427-5282-4228-b062-02cb90801f1f,
  abstract     = {<p>A new generation of potent hDHODH inhibitors designed by a scaffold-hopping replacement of the quinolinecarboxylate moiety of brequinar, one of the most potent known hDHODH inhibitors, is presented here. Their general structure is characterized by a biphenyl moiety joined through an amide bridge with an acidic hydroxyazole scaffold (hydroxylated thiadiazole, pyrazole and triazole). Molecular modelling suggested that these structures should adopt a brequinar-like binding mode involving interactions with subsites 1, 2 and 4 of the hDHODH binding site. Initially, the inhibitory activity of the compounds was studied on recombinant hDHODH. The most potent compound of the series in the enzymatic assays was the thiadiazole analogue 4 (IC<sub>50</sub>16 nM). The activity was found to be dependent on the fluoro substitution pattern at the biphenyl moiety as well as on the choice/substitution of the heterocyclic ring. Structure determination of hDHODH co-crystallized with one representative compound from each series (4, 5 and 6) confirmed the brequinar-like binding mode as suggested by modelling. The specificity of the observed effects of the compound series was tested in cell-based assays for antiproliferation activity using Jurkat cells and PHA-stimulated PBMC. These tests were also verified by addition of exogenous uridine to the culture medium. In particular, the triazole analogue 6 (IC<sub>50</sub>against hDHODH: 45 nM) exerted potent in vitro antiproliferative and immunosuppressive activity without affecting cell survival.</p>},
  author       = {Sainas, Stefano and Pippione, Agnese C. and Giorgis, Marta and Lupino, Elisa and Goyal, Parveen and Ramondetti, Cristina and Buccinnà, Barbara and Piccinini, Marco and Braga, Rodolpho C. and Andrade, Carolina H. and Andersson, Mikael and Moritzer, Ann Christin and Friemann, Rosmarie and Mensa, Stefano and Al-Karadaghi, Salam and Boschi, Donatella and Lolli, Marco L.},
  issn         = {0223-5234},
  keyword      = {Autoimmune diseases,Bioisosterism,Brequinar,Dihydroorotate dehydrogenase (DHODH) inhibitors,Leflunomide,X-ray-crystallography},
  language     = {eng},
  pages        = {287--302},
  publisher    = {Elsevier Masson SAS},
  series       = {European Journal of Medicinal Chemistry},
  title        = {Design, synthesis, biological evaluation and X-ray structural studies of potent human dihydroorotate dehydrogenase inhibitors based on hydroxylated azole scaffolds},
  url          = {http://dx.doi.org/10.1016/j.ejmech.2017.02.017},
  volume       = {129},
  year         = {2017},
}