Synthesis and in vitro Metabolic Stability of Sterically Shielded Antimycobacterial Phenylalanine Amides
Abstract: Nα‐aroyl‐N‐aryl‐phenylalanine amides (AAPs) are RNA polymerase inhibitors with activity against Mycobacterium tuberculosis and non‐tuberculous mycobacteria. We observed that AAPs rapidly degrade in microsomal suspensions, suggesting that avoiding hepatic metabolism is critical for their effectiveness in vivo. As both amide bonds are potential metabolic weak points of the molecule, we synthesized 16 novel AAP analogs in which the amide bonds are shielded by methyl or fluoro substituents in close proximity. Some derivatives show improved microsomal stability, while being plasma‐stable and non‐cytotoxic. In parallel with the metabolic stability studies, the antimycobacterial activity of the AAPs against Mycobacterium tuberculosis, Mycobacterium abscessus, Mycobacterium avium and Mycobacterium intracellulare was determined. The stability data are discussed in relation to the antimycobacterial activity of the panel of compounds and reveal that the concept of steric shielding of the anilide groups by a fluoro substituent has the potential to improve the stability and bioavailability of AAPs.
- Location
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Deutsche Nationalbibliothek Frankfurt am Main
- Extent
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Online-Ressource
- Language
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Englisch
- Bibliographic citation
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Synthesis and in vitro Metabolic Stability of Sterically Shielded Antimycobacterial Phenylalanine Amides ; day:29 ; month:02 ; year:2024 ; extent:11
ChemMedChem ; (29.02.2024) (gesamt 11)
- Creator
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Lang, Markus
Ganapathy, Uday S.
Brinkmann, Lea
Seidel, Rüdiger W.
Goddard, Richard
Erdmann, Frank
Dick, Thomas
Richter, Adrian
- DOI
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10.1002/cmdc.202300593
- URN
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urn:nbn:de:101:1-2024030114055586218552
- Rights
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Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
- Last update
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14.08.2025, 10:45 AM CEST
Data provider
Deutsche Nationalbibliothek. If you have any questions about the object, please contact the data provider.
Associated
- Lang, Markus
- Ganapathy, Uday S.
- Brinkmann, Lea
- Seidel, Rüdiger W.
- Goddard, Richard
- Erdmann, Frank
- Dick, Thomas
- Richter, Adrian
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Development of Sterically Hindered and Basic Sodium Amides for Catalytic Hydrogen Isotope Exchange
Synthesis of Sterically Encumbered Alkaline‐Earth Metal Amides Applying the In Situ Grignard Reagent Formation
Synthesis and characterization of Nα-aroyl-N-aryl-phenylalanine amides and their activity against mycobacteria
Nα ‐Aroyl‐ N ‐Aryl‐Phenylalanine Amides: A Promising Class of Antimycobacterial Agents Targeting the RNA Polymerase
Structurally Defined Ring‐Opening and Insertion of Pinacolborane into Aluminium‐Nitrogen Bonds of Sterically Demanding Dialkylaluminium Amides
The stability and assembly of sterically stabilized non-polar nanoparticles
The stability and assembly of sterically stabilized non-polar nanoparticles
Weinreb Amides
Biosynthesis of L-phenylalanine derived compounds by metabolic engineering in "Saccharomyces cerevisiae"
Metabolic transcription analysis of engineered Escherichia coli strains that overproduce L-phenylalanine
Nms‐Amides: An Amine Protecting Group with Unique Stability and Selectivity
Les Amides, I
Development of Sterically Hindered and Basic Sodium Amides for Catalytic Hydrogen Isotope Exchange
Synthesis of Sterically Encumbered Alkaline‐Earth Metal Amides Applying the In Situ Grignard Reagent Formation
Synthesis and characterization of Nα-aroyl-N-aryl-phenylalanine amides and their activity against mycobacteria
Nα ‐Aroyl‐ N ‐Aryl‐Phenylalanine Amides: A Promising Class of Antimycobacterial Agents Targeting the RNA Polymerase
Structurally Defined Ring‐Opening and Insertion of Pinacolborane into Aluminium‐Nitrogen Bonds of Sterically Demanding Dialkylaluminium Amides
The stability and assembly of sterically stabilized non-polar nanoparticles
The stability and assembly of sterically stabilized non-polar nanoparticles
Weinreb Amides
Biosynthesis of L-phenylalanine derived compounds by metabolic engineering in "Saccharomyces cerevisiae"
Metabolic transcription analysis of engineered Escherichia coli strains that overproduce L-phenylalanine
Nms‐Amides: An Amine Protecting Group with Unique Stability and Selectivity