Article (Scientific journals)
Design, Synthesis, and Evaluation of Novel Pyruvate Dehydrogenase Kinase Inhibitors
Arslan, Deniz; Schoumacher, Matthieu; Dilly, Sébastien et al.
2023In Medicinal Chemistry, 19 (3), p. 276-296
Peer Reviewed verified by ORBi
 

Files


Full Text
Article med_chem2022.pdf
Publisher postprint (2.38 MB)
Download

All documents in ORBi are protected by a user license.

Send to



Details



Keywords :
Drug Discovery; Medicinal Chemistry; Synthesis; Pharmacology
Abstract :
[en] The present work describes the synthesis and the biological evaluation of novel compounds acting as pyruvate dehydrogenase kinase (PDK) inhibitors. These drugs should become a new therapeutic approach for the treatment of pathologies improved by the control of the blood lactate level. Methods: Four series of compounds belonging to N-(4-(N-alkyl/aralkylsulfamoyl)phenyl)-2-methylpropanamides and to 1,2,4-benzothiadiazine 1,1-dioxides were prepared and evaluated as PDK inhibitors. Results: The newly synthesized N-(4-(N-alkyl/aralkylsulfamoyl)phenyl)-2-methylpropanamides structurally related to previously reported reference compounds 4 and 5 were found to be potent PDK inhibitors (i.e. 10d: IC50 = 41 nM). 1,2,4-Benzothiadiazine 1,1-dioxides carrying a (methyl/trifluoromethyl)-propanamide moiety at the 6-position were also designed as conformationally restricted ring-closed analogues of N-(4-(N-alkyl/aralkylsulfamoyl)phenyl)-2-hydroxy-2-methylpropanamides. Most of them were found to be less potent than their ring-opened analogues. Interestingly, the best choice of hydrocarbon side chain at the 4-position was the benzyl chain, providing 11c (IC50 = 3.6 µM) belonging to “unsaturated” 1,2,4-benzothiadiazine 1,1-dioxides, and 12c (IC50 = 0.5 µM) belonging to “saturated’ 1,2,4-benzothiadiazine 1,1-dioxides. Conclusion: This work showed that ring-closed analogues of N-(4-(N-alkyl/aralkylsulfamoyl)phenyl)-2-hydroxy-2-methylpropanamides were less active as PDK inhibitors than their corresponding ring-opened analogues. However, the introduction of a bulkier substituent at the 4-position of the 1,2,4-benzothiadiazine 1,1-dioxide core structure, such as a benzyl or a phenethyl side chain, was allowed, opening the way to the design of new inhibitors with improved PDK inhibitory activity.
Research center :
CIRM - Centre Interdisciplinaire de Recherche sur le Médicament - ULiège
Disciplines :
Pharmacy, pharmacology & toxicology
Author, co-author :
Arslan, Deniz ;  Université de Liège - ULiège > Unités de recherche interfacultaires > Centre Interdisciplinaire de Recherche sur le Médicament (CIRM)
Schoumacher, Matthieu ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie cellulaire et moléculaire
Dilly, Sébastien ;  Université de Liège - ULiège > Unités de recherche interfacultaires > GIGA-Research
Elmoualij, Benaïssa ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques
Zorzi, Danièle ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques
Quatresooz, Pascale  ;  Centre Hospitalier Universitaire de Liège - CHU > > Service dermatopathologie
Lambert, Vincent  ;  Centre Hospitalier Universitaire de Liège - CHU > > Service d'ophtalmologie
Noël, Agnès ;  Université de Liège - ULiège > GIGA > GIGA Cancer
Pirotte, Bernard  ;  Université de Liège - ULiège > Unités de recherche interfacultaires > Centre Interdisciplinaire de Recherche sur le Médicament (CIRM)
De Tullio, Pascal ;  Université de Liège - ULiège > Unités de recherche interfacultaires > Centre Interdisciplinaire de Recherche sur le Médicament (CIRM)
Language :
English
Title :
Design, Synthesis, and Evaluation of Novel Pyruvate Dehydrogenase Kinase Inhibitors
Publication date :
2023
Journal title :
Medicinal Chemistry
ISSN :
1573-4064
Publisher :
Bentham Science Publishers Ltd.
Volume :
19
Issue :
3
Pages :
276-296
Peer reviewed :
Peer Reviewed verified by ORBi
Name of the research project :
Design, Synthesis, and Evaluation of Novel Pyruvate Dehydrogenase Kinase Inhibitors
Funders :
ULiège - Université de Liège [BE]
Available on ORBi :
since 30 August 2022

Statistics


Number of views
130 (22 by ULiège)
Number of downloads
112 (7 by ULiège)

Scopus citations®
 
0
Scopus citations®
without self-citations
0
OpenCitations
 
0

Bibliography


Similar publications



Contact ORBi