Synthesis and kinetic evaluation of analogs of (E)-4-amino-3-methylbut-2-en-1-yl diphosphate, a potent inhibitor of the IspH metalloenzyme
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...
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Académie des sciences
2023-12-01
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| Series: | Comptes Rendus. Chimie |
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| Online Access: | https://comptes-rendus.academie-sciences.fr/chimie/articles/10.5802/crchim.254/ |
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| author | Petit, Benoît Eric Jobelius, Hannah Bianchino, Gabriella Ines Guérin, Mélina Borel, Franck Chaignon, Philippe Seemann, Myriam |
| author_facet | Petit, Benoît Eric Jobelius, Hannah Bianchino, Gabriella Ines Guérin, Mélina Borel, Franck Chaignon, Philippe Seemann, Myriam |
| author_sort | Petit, Benoît Eric |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-f299621987714a9bbf078465c61d6423 |
| institution | Kabale University |
| issn | 1878-1543 |
| language | English |
| publishDate | 2023-12-01 |
| publisher | Académie des sciences |
| record_format | Article |
| series | Comptes Rendus. Chimie |
| spelling | doaj-art-f299621987714a9bbf078465c61d64232025-02-07T13:38:54ZengAcadémie des sciencesComptes Rendus. Chimie1878-15432023-12-0126S3799210.5802/crchim.25410.5802/crchim.254Synthesis and kinetic evaluation of analogs of (E)-4-amino-3-methylbut-2-en-1-yl diphosphate, a potent inhibitor of the IspH metalloenzymePetit, Benoît Eric0Jobelius, Hannah1https://orcid.org/0000-0003-0715-8751Bianchino, Gabriella Ines2https://orcid.org/0000-0002-6553-6063Guérin, Mélina3https://orcid.org/0009-0006-5986-5828Borel, Franck4https://orcid.org/0000-0002-8905-5336Chaignon, Philippe5https://orcid.org/0009-0002-1970-5716Seemann, Myriam6https://orcid.org/0000-0002-2615-1574Equipe Chimie Biologique et Applications Thérapeutiques, Institut de Chimie de Strasbourg, UMR 7177, Université de Strasbourg/CNRS, 4, rue Blaise Pascal, 67070 Strasbourg, FranceEquipe Chimie Biologique et Applications Thérapeutiques, Institut de Chimie de Strasbourg, UMR 7177, Université de Strasbourg/CNRS, 4, rue Blaise Pascal, 67070 Strasbourg, FranceEquipe Chimie Biologique et Applications Thérapeutiques, Institut de Chimie de Strasbourg, UMR 7177, Université de Strasbourg/CNRS, 4, rue Blaise Pascal, 67070 Strasbourg, FranceEquipe Chimie Biologique et Applications Thérapeutiques, Institut de Chimie de Strasbourg, UMR 7177, Université de Strasbourg/CNRS, 4, rue Blaise Pascal, 67070 Strasbourg, FranceUniv. Grenoble Alpes, CEA, CNRS, IBS, F-38000 Grenoble, FranceEquipe Chimie Biologique et Applications Thérapeutiques, Institut de Chimie de Strasbourg, UMR 7177, Université de Strasbourg/CNRS, 4, rue Blaise Pascal, 67070 Strasbourg, FranceEquipe Chimie Biologique et Applications Thérapeutiques, Institut de Chimie de Strasbourg, UMR 7177, Université de Strasbourg/CNRS, 4, rue Blaise Pascal, 67070 Strasbourg, FranceOur 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.https://comptes-rendus.academie-sciences.fr/chimie/articles/10.5802/crchim.254/MEP pathwayIspHLytBIron–sulfur clustersInhibitor(<i>E</i>)-4-amino-3-methylbut-2-en-1-yl diphosphateAnti-infectives |
| spellingShingle | Petit, Benoît Eric Jobelius, Hannah Bianchino, Gabriella Ines Guérin, Mélina Borel, Franck Chaignon, Philippe Seemann, Myriam 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 MEP pathway IspH LytB Iron–sulfur clusters Inhibitor (<i>E</i>)-4-amino-3-methylbut-2-en-1-yl diphosphate Anti-infectives |
| title | Synthesis and kinetic evaluation of analogs of (E)-4-amino-3-methylbut-2-en-1-yl diphosphate, a potent inhibitor of the IspH metalloenzyme |
| title_full | Synthesis and kinetic evaluation of analogs of (E)-4-amino-3-methylbut-2-en-1-yl diphosphate, a potent inhibitor of the IspH metalloenzyme |
| title_fullStr | Synthesis and kinetic evaluation of analogs of (E)-4-amino-3-methylbut-2-en-1-yl diphosphate, a potent inhibitor of the IspH metalloenzyme |
| title_full_unstemmed | Synthesis and kinetic evaluation of analogs of (E)-4-amino-3-methylbut-2-en-1-yl diphosphate, a potent inhibitor of the IspH metalloenzyme |
| title_short | Synthesis and kinetic evaluation of analogs of (E)-4-amino-3-methylbut-2-en-1-yl diphosphate, a potent inhibitor of the IspH metalloenzyme |
| title_sort | synthesis and kinetic evaluation of analogs of e 4 amino 3 methylbut 2 en 1 yl diphosphate a potent inhibitor of the isph metalloenzyme |
| topic | MEP pathway IspH LytB Iron–sulfur clusters Inhibitor (<i>E</i>)-4-amino-3-methylbut-2-en-1-yl diphosphate Anti-infectives |
| url | https://comptes-rendus.academie-sciences.fr/chimie/articles/10.5802/crchim.254/ |
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