Synthesis and kinetic evaluation of analogs of (E)-4-amino-3-methylbut-2-en-1-yl diphosphate, a potent inhibitor of the IspH metalloenzyme - Archive ouverte du site Alsace Access content directly
Journal Articles Comptes Rendus. Chimie Year : 2023

Synthesis and kinetic evaluation of analogs of (E)-4-amino-3-methylbut-2-en-1-yl diphosphate, a potent inhibitor of the IspH metalloenzyme

Abstract

Our previous research revealed that (E)-4-amino-3-methylbut-2-en-1-yl diphosphate (AMBPP) is one of the best inhibitors of IspH, a [4Fe-4S]-dependent enzyme involved in the methylerythritol phosphate pathway that is a valuable target for the discovery of new antibacterial and antiparasitic drugs as it is absent in humans. AMBPP has substantial limitations for drug development due to its poor metabolic stability. Here, we investigate the replacement of the diphosphate moiety of AMBPP by more stable mimics: sulfonate, phosphonate or phosphinophosphonate. After synthesis of the derivatives, enzymatic assays demonstrated that none of these AMBPP analogs is an efficient IspH inhibitor.
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Dates and versions

hal-04476071 , version 1 (24-02-2024)

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Benoît Eric Petit, Hannah Jobelius, Gabriella Ines Bianchino, Mélina Guérin, Franck Borel, et al.. Synthesis and kinetic evaluation of analogs of (E)-4-amino-3-methylbut-2-en-1-yl diphosphate, a potent inhibitor of the IspH metalloenzyme. Comptes Rendus. Chimie, 2023, 26 (S3), pp.1-14. ⟨10.5802/crchim.254⟩. ⟨hal-04476071⟩
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