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Synthesis, biological evaluation, and molecular docking studies of aldotetronic acid-based LpxC inhibitors

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Synthesis, biological evaluation, and molecular docking studies of aldotetronic acid-based LpxC inhibitors. / Wimmer, Stefan; Hoff, Katharina; Martin, Benedikt; Grewer, Martin; Denni, Laura; Lascorz Massanet, Raquel; Raimondi, Maria Valeria; Bülbül, Emre F; Melesina, Jelena; Hotop, Sven-Kevin; Haupenthal, Jörg; Rohde, Holger; Heisig, Peter; Hirsch, Anna K H; Brönstrup, Mark; Sippl, Wolfgang; Holl, Ralph.

in: BIOORG CHEM, Jahrgang 131, 106331, 02.2023.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Wimmer, S, Hoff, K, Martin, B, Grewer, M, Denni, L, Lascorz Massanet, R, Raimondi, MV, Bülbül, EF, Melesina, J, Hotop, S-K, Haupenthal, J, Rohde, H, Heisig, P, Hirsch, AKH, Brönstrup, M, Sippl, W & Holl, R 2023, 'Synthesis, biological evaluation, and molecular docking studies of aldotetronic acid-based LpxC inhibitors', BIOORG CHEM, Jg. 131, 106331. https://doi.org/10.1016/j.bioorg.2022.106331

APA

Wimmer, S., Hoff, K., Martin, B., Grewer, M., Denni, L., Lascorz Massanet, R., Raimondi, M. V., Bülbül, E. F., Melesina, J., Hotop, S-K., Haupenthal, J., Rohde, H., Heisig, P., Hirsch, A. K. H., Brönstrup, M., Sippl, W., & Holl, R. (2023). Synthesis, biological evaluation, and molecular docking studies of aldotetronic acid-based LpxC inhibitors. BIOORG CHEM, 131, [106331]. https://doi.org/10.1016/j.bioorg.2022.106331

Vancouver

Wimmer S, Hoff K, Martin B, Grewer M, Denni L, Lascorz Massanet R et al. Synthesis, biological evaluation, and molecular docking studies of aldotetronic acid-based LpxC inhibitors. BIOORG CHEM. 2023 Feb;131. 106331. https://doi.org/10.1016/j.bioorg.2022.106331

Bibtex

@article{dd78a02e7bff40d2a20c8065309455ad,
title = "Synthesis, biological evaluation, and molecular docking studies of aldotetronic acid-based LpxC inhibitors",
abstract = "In order to develop novel inhibitors of the bacterial deacetylase LpxC bearing a substituent to target the UDP binding site of the enzyme, a series of aldotetronic acid-based hydroxamic acids was accessed in chiral pool syntheses starting from 4,6-O-benzylidene-d-glucose and l-arabinitol. The synthesized hydroxamic acids were tested for LpxC inhibitory activity in vitro, revealing benzyl ether 17a ((2S,3S)-4-(benzyloxy)-N,3-dihydroxy-2-[(4-{[4-(morpholinomethyl)phenyl]ethynyl}benzyl)oxy]butanamide) as the most potent LpxC inhibitor. This compound was additionally tested for antibacterial activity against a panel of clinically relevant Gram-negative bacteria, bacterial uptake, and susceptibility to efflux pumps. Molecular docking studies were performed to rationalize the observed structure-activity relationships.",
author = "Stefan Wimmer and Katharina Hoff and Benedikt Martin and Martin Grewer and Laura Denni and {Lascorz Massanet}, Raquel and Raimondi, {Maria Valeria} and B{\"u}lb{\"u}l, {Emre F} and Jelena Melesina and Sven-Kevin Hotop and J{\"o}rg Haupenthal and Holger Rohde and Peter Heisig and Hirsch, {Anna K H} and Mark Br{\"o}nstrup and Wolfgang Sippl and Ralph Holl",
note = "Copyright {\textcopyright} 2022 Elsevier Inc. All rights reserved.",
year = "2023",
month = feb,
doi = "10.1016/j.bioorg.2022.106331",
language = "English",
volume = "131",
journal = "BIOORG CHEM",
issn = "0045-2068",
publisher = "Academic Press Inc.",

}

RIS

TY - JOUR

T1 - Synthesis, biological evaluation, and molecular docking studies of aldotetronic acid-based LpxC inhibitors

AU - Wimmer, Stefan

AU - Hoff, Katharina

AU - Martin, Benedikt

AU - Grewer, Martin

AU - Denni, Laura

AU - Lascorz Massanet, Raquel

AU - Raimondi, Maria Valeria

AU - Bülbül, Emre F

AU - Melesina, Jelena

AU - Hotop, Sven-Kevin

AU - Haupenthal, Jörg

AU - Rohde, Holger

AU - Heisig, Peter

AU - Hirsch, Anna K H

AU - Brönstrup, Mark

AU - Sippl, Wolfgang

AU - Holl, Ralph

N1 - Copyright © 2022 Elsevier Inc. All rights reserved.

PY - 2023/2

Y1 - 2023/2

N2 - In order to develop novel inhibitors of the bacterial deacetylase LpxC bearing a substituent to target the UDP binding site of the enzyme, a series of aldotetronic acid-based hydroxamic acids was accessed in chiral pool syntheses starting from 4,6-O-benzylidene-d-glucose and l-arabinitol. The synthesized hydroxamic acids were tested for LpxC inhibitory activity in vitro, revealing benzyl ether 17a ((2S,3S)-4-(benzyloxy)-N,3-dihydroxy-2-[(4-{[4-(morpholinomethyl)phenyl]ethynyl}benzyl)oxy]butanamide) as the most potent LpxC inhibitor. This compound was additionally tested for antibacterial activity against a panel of clinically relevant Gram-negative bacteria, bacterial uptake, and susceptibility to efflux pumps. Molecular docking studies were performed to rationalize the observed structure-activity relationships.

AB - In order to develop novel inhibitors of the bacterial deacetylase LpxC bearing a substituent to target the UDP binding site of the enzyme, a series of aldotetronic acid-based hydroxamic acids was accessed in chiral pool syntheses starting from 4,6-O-benzylidene-d-glucose and l-arabinitol. The synthesized hydroxamic acids were tested for LpxC inhibitory activity in vitro, revealing benzyl ether 17a ((2S,3S)-4-(benzyloxy)-N,3-dihydroxy-2-[(4-{[4-(morpholinomethyl)phenyl]ethynyl}benzyl)oxy]butanamide) as the most potent LpxC inhibitor. This compound was additionally tested for antibacterial activity against a panel of clinically relevant Gram-negative bacteria, bacterial uptake, and susceptibility to efflux pumps. Molecular docking studies were performed to rationalize the observed structure-activity relationships.

U2 - 10.1016/j.bioorg.2022.106331

DO - 10.1016/j.bioorg.2022.106331

M3 - SCORING: Journal article

C2 - 36587505

VL - 131

JO - BIOORG CHEM

JF - BIOORG CHEM

SN - 0045-2068

M1 - 106331

ER -