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α‐Unsaturated 3‐Amino‐1‐carboxymethyl‐β‐lactams as bacterial PBP inhibitors : synthesis and biochemical assessment

(2019) CHEMISTRY-A EUROPEAN JOURNAL. 25(70). p.16128-16140
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Abstract
Innovative monocyclic beta-lactam entities create opportunities in the battle against resistant bacteria because of their PBP acylation potential, intrinsically high beta-lactamase stability and compact scaffold. alpha-Benzylidene-substituted 3-amino-1-carboxymethyl-beta-lactams were recently shown to be potent PBP inhibitors and constitute eligible anchor points for synthetic elaboration of the chemical space around the central beta-lactam ring. The present study discloses a 12-step synthesis of ten alpha-arylmethylidenecarboxylates using a microwave-assisted Wittig olefination as the crucial reaction step. The library was designed aiming at enhanced beta-lactam electrophilicity and extended electron flow after enzymatic attack. Additionally, increased beta-lactamase stability and intermolecular target interaction were envisioned by tackling both the substitution pattern of the aromatic ring and the beta-lactam C4-position. The significance of alpha-unsaturation was validated and the R39/PBP3 inhibitory potency shown to be augmented the most through decoration of the aromatic ring with electron-withdrawing groups. Furthermore, ring cleavage by representative beta-lactamases was ruled out, providing new insights in the SAR landscape of monocyclic beta-lactams as eligible PBP or beta-lactamase inhibitors.
Keywords
General Chemistry, antibiotics, beta-lactams, biological activity, semi-empirical calculations, Wittig reaction, PENICILLIN-BINDING PROTEINS, ENANTIOSELECTIVE SYNTHESIS, PEPTIDOGLYCAN STRUCTURE, SULFAZECIN ANALOGS, MICROWAVE-OVENS, WITTIG REACTION, ANTIBIOTICS, 2-OXOCEPHEMS, REACTIVITY, MECHANISM

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Citation

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MLA
Decuyper, Lena, et al. “Α‐Unsaturated 3‐Amino‐1‐carboxymethyl‐β‐lactams as Bacterial PBP Inhibitors : Synthesis and Biochemical Assessment.” CHEMISTRY-A EUROPEAN JOURNAL, vol. 25, no. 70, 2019, pp. 16128–40, doi:10.1002/chem.201904139.
APA
Decuyper, L., Magdalenic, K., Verstraete, M., Jukič, M., Sosič, I., Sauvage, E., … D’hooghe, M. (2019). α‐Unsaturated 3‐Amino‐1‐carboxymethyl‐β‐lactams as bacterial PBP inhibitors : synthesis and biochemical assessment. CHEMISTRY-A EUROPEAN JOURNAL, 25(70), 16128–16140. https://doi.org/10.1002/chem.201904139
Chicago author-date
Decuyper, Lena, Katarina Magdalenic, Marie Verstraete, Marko Jukič, Izidor Sosič, Eric Sauvage, Ana Maria Amoroso, et al. 2019. “Α‐Unsaturated 3‐Amino‐1‐carboxymethyl‐β‐lactams as Bacterial PBP Inhibitors : Synthesis and Biochemical Assessment.” CHEMISTRY-A EUROPEAN JOURNAL 25 (70): 16128–40. https://doi.org/10.1002/chem.201904139.
Chicago author-date (all authors)
Decuyper, Lena, Katarina Magdalenic, Marie Verstraete, Marko Jukič, Izidor Sosič, Eric Sauvage, Ana Maria Amoroso, Olivier Verlaine, Bernard Joris, Stanislav Gobec, and Matthias D’hooghe. 2019. “Α‐Unsaturated 3‐Amino‐1‐carboxymethyl‐β‐lactams as Bacterial PBP Inhibitors : Synthesis and Biochemical Assessment.” CHEMISTRY-A EUROPEAN JOURNAL 25 (70): 16128–16140. doi:10.1002/chem.201904139.
Vancouver
1.
Decuyper L, Magdalenic K, Verstraete M, Jukič M, Sosič I, Sauvage E, et al. α‐Unsaturated 3‐Amino‐1‐carboxymethyl‐β‐lactams as bacterial PBP inhibitors : synthesis and biochemical assessment. CHEMISTRY-A EUROPEAN JOURNAL. 2019;25(70):16128–40.
IEEE
[1]
L. Decuyper et al., “α‐Unsaturated 3‐Amino‐1‐carboxymethyl‐β‐lactams as bacterial PBP inhibitors : synthesis and biochemical assessment,” CHEMISTRY-A EUROPEAN JOURNAL, vol. 25, no. 70, pp. 16128–16140, 2019.
@article{8641518,
  abstract     = {Innovative monocyclic beta-lactam entities create opportunities in the battle against resistant bacteria because of their PBP acylation potential, intrinsically high beta-lactamase stability and compact scaffold. alpha-Benzylidene-substituted 3-amino-1-carboxymethyl-beta-lactams were recently shown to be potent PBP inhibitors and constitute eligible anchor points for synthetic elaboration of the chemical space around the central beta-lactam ring. The present study discloses a 12-step synthesis of ten alpha-arylmethylidenecarboxylates using a microwave-assisted Wittig olefination as the crucial reaction step. The library was designed aiming at enhanced beta-lactam electrophilicity and extended electron flow after enzymatic attack. Additionally, increased beta-lactamase stability and intermolecular target interaction were envisioned by tackling both the substitution pattern of the aromatic ring and the beta-lactam C4-position. The significance of alpha-unsaturation was validated and the R39/PBP3 inhibitory potency shown to be augmented the most through decoration of the aromatic ring with electron-withdrawing groups. Furthermore, ring cleavage by representative beta-lactamases was ruled out, providing new insights in the SAR landscape of monocyclic beta-lactams as eligible PBP or beta-lactamase inhibitors.},
  author       = {Decuyper, Lena and Magdalenic, Katarina and Verstraete, Marie and Jukič, Marko and Sosič, Izidor and Sauvage, Eric and Amoroso, Ana Maria and Verlaine, Olivier and Joris, Bernard and Gobec, Stanislav and D'hooghe, Matthias},
  issn         = {0947-6539},
  journal      = {CHEMISTRY-A EUROPEAN JOURNAL},
  keywords     = {General Chemistry,antibiotics,beta-lactams,biological activity,semi-empirical calculations,Wittig reaction,PENICILLIN-BINDING PROTEINS,ENANTIOSELECTIVE SYNTHESIS,PEPTIDOGLYCAN STRUCTURE,SULFAZECIN ANALOGS,MICROWAVE-OVENS,WITTIG REACTION,ANTIBIOTICS,2-OXOCEPHEMS,REACTIVITY,MECHANISM},
  language     = {eng},
  number       = {70},
  pages        = {16128--16140},
  title        = {α‐Unsaturated 3‐Amino‐1‐carboxymethyl‐β‐lactams as bacterial PBP inhibitors : synthesis and biochemical assessment},
  url          = {http://dx.doi.org/10.1002/chem.201904139},
  volume       = {25},
  year         = {2019},
}

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