Fiche publication
Date publication
janvier 2026
Journal
Microorganisms
Auteurs
Membres identifiés du Cancéropôle Est :
Pr GROSDEMANGE-BILLIARD Catherine
Tous les auteurs :
Allamand A, Noël-Duchesneau L, Ettelbruck C, De Luna E, Lièvremont D, Grosdemange-Billiard C
Lien Pubmed
Résumé
We report the first synthesis of IspH-directed prodrugs targeting the terminal enzyme of the 2--methyl-D-erythritol 4-phosphate (MEP) pathway, ()-4-hydroxy-3-methylbut-2-enyl diphosphate reductase (IspH or LytB). A series of alkyne and pyridine monophosphate Saligenyl (Sal) prodrugs were prepared to enhance membrane permeability by masking the phosphate group. The effects of electron-withdrawing (Cl, CF) and electron-donating (OCH, NH) substituents were examined, together with amino acid-functionalized and mutual prodrug analogs. Among the synthesized compounds, chlorine-substituted derivatives and displayed the strongest antimycobacterial activity against , surpassing isoniazid in agar diffusion assays. These results indicate that electron-withdrawing substituents accelerate prodrug hydrolysis and facilitate intracellular release of the active inhibitor. This work provides the first experimental evidence of an IspH-targeted prodrug approach, highlighting the Sal strategy as a valuable tool for delivering phosphorylated inhibitors and developing novel antimycobacterial agents acting through the MEP pathway.
Mots clés
4-hydroxy-3-methylbut-2-enyl diphosphate reductase, Mycobacterium smegmatis, antimycobacterial, cycloSaligenyl prodrug, isoniazid, isoprenoid biosynthesis
Référence
Microorganisms. 2026 01 17;14(1):
