Peptide deformylase inhibitors with activity against respiratory tract pathogens

East, Stephen P.; Beckett, R.Paul; Brookings, Daniel C.; Clements, John M.; Doel, S. M.; Keavey, Kenneth; Pain, Gilles; Smith, Helen K.; Thomas, Wayne; Thompson, Alison J.; Todd, Richard S.; Whittaker, Mark

doi:10.1016/j.bmcl.2003.10.013

Cited by 17 publications

(2 citation statements)

References 15 publications

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“…However, none of the modification produced improved activity. The isoxazole was incorporated to model the amide moiety in PDF inhibitors as hydrogen bond donor, which has been demonstrated to be important to inhibitors' activities (Clements et al, 2001;Chen et al, 2004;East et al, 2004). The decrease of the inhibitory activity should be attributable to the introduction of the alkyl chain, which influenced the steric orientation of the heteroatom of the isoxazole ring.…”

Section: Biological Activitymentioning

confidence: 99%

Synthesis and preliminary antibacterial evaluation of 2-butyl succinate-based hydroxamate derivatives containing isoxazole rings

et al. 2010

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Two series of novel 2-butyl succinate-based Hydroxamate derivatives containing isoxazole rings were synthesized, characterized and evaluated for antibacterial activity. The synthesized compounds were found to exhibit weak to moderate inhibitory activity against Staphytlococcus aureu and Klebsiellar pneumonia in vitro. All the compounds synthesized were found to be more effective against Klebsiellar pneumonia compared to Staphytlococcus aureu.

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Section: Biological Activitymentioning

confidence: 99%

Synthesis and preliminary antibacterial evaluation of 2-butyl succinate-based hydroxamate derivatives containing isoxazole rings

et al. 2010

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“…19 Moreover, Tle is extensively exploited as a building block in the design of enzyme inhibitors, peptide hormone receptor antagonists, and analogues of bioactive peptides. [20][21][22][23][24][25][26][27][28] In the present study, five new disubstituted (Xaa 1 and Tle 5 ) ascidiacyclamide analogues (Xb) [Xaa 1 : Ala (2b), Abu (3b), Val (4b), Chg (5b) and Phg (6b)] were synthesized in an effort to understand the effect of tert-butyl side chains (Tle 5 ) on conformational equilibrium (Figure 1). We first describe their structural characterization using X-ray diffraction and circular dichroism (CD) spectroscopy and then use thermodynamic parameters of conformational equilibrium to discuss the effect of the tert-butyl side chain on the conformation.…”

Section: Introductionmentioning

confidence: 99%

Effect of the powerful plasticity of the tert‐butyl side chain on the conformational equilibrium of ascidiacyclamides

Asano

Nakagawa

Miyajima

et al. 2021

Journal of Peptide Science

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Ascidiacyclamide [cyclo(-Ile 1,5 -oxazoline 2,6 -D-Val 3,7 -thiazole 4,8 -) 2 ] is a cytotoxic cyclic peptide from ascidian. Through structural analyses using monosubstituted analogues (Xaa 1 : Ala, 2-aminobutyric acid, Val, cyclohexylglycine, and phenylglycine), we previously demonstrated the conformational equilibrium between its square and folded forms. As the bulkiness of the Xaa 1 residue side chain was reduced, spontaneous folding was promoted, and the cytotoxicity decreased accordingly. In the present study, five disubstituted analogues in which a tert-leucine residue (Tle) was incorporated at the 5-position of the abovementioned monosubstituted analogues were synthesized, after which their structures were analyzed using X-ray diffraction, circular dichroism (CD) spectral measurements, and 1 H NMR-based quantitative analysis. The side chains of the Tle and Ile residues are structural isomers of one another, and the Tle residue bearing the tert-butyl group can be expected to play a role as a building block. In fact, peptides incorporating Tle 5 exhibited much less spontaneous folding than their Ile 5 counterparts in both crystal and solution. Increases in enthalpy and entropy due to the tert-butyl group during the folding process resulted in increased conformational free energy (ΔG ). The powerful plasticity of the tert-butyl group would stabilize the square form relating with cytotoxicity.

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Preferred Conformations of Peptides Containing tert‐Leucine, a Sterically Demanding, Lipophilic α‐Amino Acid with a Quaternary Side‐Chain C^β Atom

Formaggio

Baldini

Moretto

et al. 2005

Chemistry A European J

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Terminally protected homopeptides of tert-leucine, from the dimer to the hexamer, co-oligopeptides of tert-leucine in combination with alpha-aminoisobutyric acid or glycine residues up to the hexamer level, and simple dipeptides representing known scaffolds for catalysts in asymmetric organic reactions were prepared by solution methods and fully characterized. The results of conformation analysis, performed by use of FT-IR absorption, NMR, CD, and X-ray diffraction techniques, indicate that this hydrophobic alpha-amino acid with tetrasubstitution at the Cbeta atom is structurally versatile. We show that it prefers extended or semiextended conformations, but can also be accommodated in folded structures, provided that these are biased by the presence of helicogenic residues. The current large-scale production of Tle, combined with its conformational preferences unravelled in this work, should make this bulky, hydrophobic, Calpha-trisubstituted alpha-amino acid a regular building block of any strategy seeking to tailor peptides with improved catalytic and pharmacological properties.

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Peptide deformylase inhibitors with activity against respiratory tract pathogens

Cited by 17 publications

References 15 publications

Synthesis and preliminary antibacterial evaluation of 2-butyl succinate-based hydroxamate derivatives containing isoxazole rings

Synthesis and preliminary antibacterial evaluation of 2-butyl succinate-based hydroxamate derivatives containing isoxazole rings

Effect of the powerful plasticity of the tert‐butyl side chain on the conformational equilibrium of ascidiacyclamides

Preferred Conformations of Peptides Containing tert‐Leucine, a Sterically Demanding, Lipophilic α‐Amino Acid with a Quaternary Side‐Chain C^β Atom

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Peptide deformylase inhibitors with activity against respiratory tract pathogens

Cited by 17 publications

References 15 publications

Synthesis and preliminary antibacterial evaluation of 2-butyl succinate-based hydroxamate derivatives containing isoxazole rings

Synthesis and preliminary antibacterial evaluation of 2-butyl succinate-based hydroxamate derivatives containing isoxazole rings

Effect of the powerful plasticity of the tert‐butyl side chain on the conformational equilibrium of ascidiacyclamides

Preferred Conformations of Peptides Containing tert‐Leucine, a Sterically Demanding, Lipophilic α‐Amino Acid with a Quaternary Side‐Chain Cβ Atom

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Preferred Conformations of Peptides Containing tert‐Leucine, a Sterically Demanding, Lipophilic α‐Amino Acid with a Quaternary Side‐Chain C^β Atom