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Medicinal Chemistry

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ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

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Research Article

Design, Synthesis, and Evaluation of Novel Pyruvate Dehydrogenase Kinase Inhibitors

Author(s): Deniz Arslan, Matthieu Schoumacher, Sébastien Dilly, Benaïssa Elmoualij, Danièle Zorzi, Pascale Quatresooz, Vincent Lambert, Agnès Noël, Bernard Pirotte* and Pascal de Tullio

Volume 19, Issue 3, 2023

Published on: 03 October, 2022

Page: [276 - 296] Pages: 21

DOI: 10.2174/1573406418666220819102627

Price: $65

Abstract

Aims: 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 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.

Keywords: Pyruvate dehydrogenase kinase inhibitor, pyruvate dehydrogenase complex, lactate, conformationally restricted analogues, benzothiadiazine dioxides, 2-hydroxy-2-(methyl/trifluoromethyl)propanamides.

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