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Hydroxyazole scaffo...
Hydroxyazole scaffold-based Plasmodium falciparum dihydroorotate dehydrogenase inhibitors : Synthesis, biological evaluation and X-ray structural studies
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- Pippione, Agnese C. (author)
- University of Turin
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- Sainas, Stefano (author)
- University of Turin
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- Goyal, Parveen, 1984 (author)
- Gothenburg University,Göteborgs universitet,University of Gothenburg,Institute for Stem Cell Biology and Regenerative Medicine (inStem),Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology
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- Fritzson, Ingela (author)
- Magle Chemoswed AB
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- Cassiano, Gustavo C. (author)
- University of Campinas
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- Giraudo, Alessandro (author)
- University of Turin
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- Giorgis, Marta (author)
- University of Turin
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- Tavella, Tatyana A. (author)
- University of Campinas
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- Bagnati, Renzo (author)
- Mario Negri Institute for Pharmacological Research
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- Rolando, Barbara (author)
- University of Turin
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- Caing Carlsson, Rhawnie (author)
- Gothenburg University,Göteborgs universitet,University of Gothenburg,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology
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- Costa, Fabio T.M. (author)
- University of Campinas
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- Andrade, Carolina Horta (author)
- Federal University of Goiás
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- Al-Karadaghi, Salam (author)
- Lund University,Lunds universitet,Biokemi och Strukturbiologi,Centrum för Molekylär Proteinvetenskap,Kemiska institutionen,Institutioner vid LTH,Lunds Tekniska Högskola,Biochemistry and Structural Biology,Center for Molecular Protein Science,Department of Chemistry,Departments at LTH,Faculty of Engineering, LTH
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- Boschi, Donatella (author)
- University of Turin
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- Friemann, Rosmarie, 1975 (author)
- Gothenburg University,Göteborgs universitet,University of Gothenburg,Institutionen för kemi och molekylärbiologi,CARe - Centrum för antibiotikaresistensforskning,Department of Chemistry and Molecular Biology,Centre for antibiotic resistance research, CARe
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- Lolli, Marco L. (author)
- University of Turin
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(creator_code:org_t)
- Elsevier BV, 2019
- 2019
- English 15 s.
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In: European Journal of Medicinal Chemistry. - : Elsevier BV. - 0223-5234 .- 1768-3254. ; 163, s. 266-280
- Related links:
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http://dx.doi.org/10...
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Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medicinal Chemistry (hsv//eng)
- NATURVETENSKAP -- Biologi -- Strukturbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Structural Biology (hsv//eng)
- NATURVETENSKAP -- Kemi -- Organisk kemi (hsv//swe)
- NATURAL SCIENCES -- Chemical Sciences -- Organic Chemistry (hsv//eng)
Keyword
- Bioisosterism
- Dihydroorotate dehydrogenase (DHODH) inhibitors
- Malaria
- Plasmodium falciparum
- Pyrazole
- Scaffold hopping
- X-ray-crystallography
Publication and Content Type
- art (subject category)
- ref (subject category)
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- By the author/editor
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Pippione, Agnese ...
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Sainas, Stefano
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Goyal, Parveen, ...
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Fritzson, Ingela
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Cassiano, Gustav ...
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Giraudo, Alessan ...
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show more...
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Giorgis, Marta
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Tavella, Tatyana ...
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Bagnati, Renzo
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Rolando, Barbara
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Caing Carlsson, ...
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Costa, Fabio T.M ...
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Andrade, Carolin ...
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Al-Karadaghi, Sa ...
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Boschi, Donatell ...
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Friemann, Rosmar ...
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Lolli, Marco L.
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Medicinal Chemis ...
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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and Structural Biolo ...
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Chemical Science ...
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and Organic Chemistr ...
- Articles in the publication
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European Journal ...
- By the university
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Lund University
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University of Gothenburg