558471-77-5

Upstream product

• 558471-75-3 C₃₅H₄₉N₅O₁₁ 
• 1542206-86-9 C₄₁H₄₈F₅N₅O₁₁ 
• 558471-74-2 tert-butyl (S)-2-((S)-2-(((S)-1-((S)-2-(((S)-2-(((benzyloxy)carbonyl)amino)-3-oxo-3-(2-oxo-2-phenylethoxy)propoxy)carbonyl)pyrrolidin-1-yl)-1-oxopropan-2-yl)carbamoyl)piperidine-1-carbonyl)pyrrolidine-1-carboxylate 
• 502964-81-0 2-((S)-2-(((benzyloxy)carbonyl)amino)-3-oxo-3-(2-oxo-2-phenylethoxy)propyl) 1-(tert-butyl) (S)-pyrrolidine-1,2-dicarboxylate 
• 1145-80-8 N-(benzyloxycarbonyl)-L-serine 
• 1542206-70-1 C₂₄H₂₇N₂O₇⁽¹⁺⁾*C₂F₃O₂^(1-) 
• 502964-96-7 C₁₉H₃₁N₃O₆ 
• 751477-87-9 C₃₆H₄₀F₅N₅O₉ 
• 1256162-00-1 C₃₅H₄₉N₅O₁₁ 
• 505-18-0 2,3,4,5-tetrahydropyridine 
• 2156-71-0 N-chloropiperidine 
• 110-89-4 piperidine 

Downstream Products

• 1256239-32-3 C₃₈H₅₁FN₆O₈ 

Relevant academic research and scientific papers

Restriction of the conformational dynamics of the cyclic acyldepsipeptide antibiotics improves their antibacterial activity

The cyclic acyldepsipeptide (ADEP) antibiotics are a new class of antibacterial agents that kill bacteria via a mechanism that is distinct from all clinically used drugs. These molecules bind and dysregulate the activity of the ClpP peptidase. The potential of these antibiotics as antibacterial drugs has been enhanced by the elimination of pharmacological liabilities through medicinal chemistry efforts. Here, we demonstrate that the ADEP conformation observed in the ADEP-ClpP crystal structure is fortified by transannular hydrogen bonding and can be further stabilized by judicious replacement of constituent amino acids within the peptidolactone core structure with more conformationally constrained counterparts. Evidence supporting constraint of the molecule into the bioactive conformer was obtained by measurements of deuterium-exchange kinetics of hydrogens that were proposed to be engaged in transannular hydrogen bonds. We show that the rigidified ADEP analogs bind and activate ClpP at lower concentrations in vitro. Remarkably, these compounds have up to 1200-fold enhanced antibacterial activity when compared to those with the peptidolactone core structure common to two ADEP natural products. This study compellingly demonstrates how rational modulation of conformational dynamics may be used to improve the bioactivities of natural products.

ENOPEPTINS, USES THEREOF, AND METHODS OF SYNTHESIS THERETO

Provided herein are inventive enopeptin compounds of Formula (I): and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Further provided are methods of preparation, use, and treatment.

Diversity-oriented synthesis of cyclic acyldepsipeptides leads to the discovery of a potent antibacterial agent

A class of cyclic acyldepsipeptide antibiotics collectively known as the enopeptins has recently attracted much attention because of their activity against multidrug-resistant bacteria, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis. These antibiotics are further distinguished by their novel mechanism of action in which they bind and deregulate the tightly controlled activity of the cytoplasmic protease ClpP. Although the natural products have poor pharmacological properties, a synthetic derivative called acyldepsipeptide 4 (ADEP 4) showed remarkable antibacterial activity both in vitro and in mouse models of bacterial infections. A novel route to the ADEP 4 peptidolactone core structure, featuring the Joullié-Ugi three-component reaction, was developed. This multicomponent reaction and a related multicomponent reaction, the Ugi four-component reaction, were used to prepare analogs that were designed using the principles of conformational analysis. These cyclic acyldepsipeptides were tested for their activity against drug-resistant, clinical isolates of Staphylococci and Enterococci. One ADEP 4 analog in which the pipecolate was replaced by 4-methyl pipecolate exhibited in vitro antibacterial activity against Enterococci that was fourfold higher than the parent compound.