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Stereo-selective synthesis, structural and antibacterial studies of novel glycosylated β2,3-amino acid analogues

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Abstract

Ten β-lactam derivatives (6a–j) with an O-phenyl group at C-2, a glycoside at C-3 and various substituted phenyl rings on the nitrogen, were formed via a series of reactions starting with the glycoside precursors, functionalizing this to the aldehyde, forming the imines and finally the lactams, which were modified, removing the benzyl group on the glycoside producing a further set of lactams (7a–j) and converting them to the β2,3 amino acids (8a–j) in the final stage of the synthesis. The synthesis and structural elucidation of the three sets of compounds are discussed here. In addition, the crystal structure of 6e is also discussed, which shows the absolute configuration of the molecule to be 2S,3R. The Hirshfeld interactions are calculated to be Cl···H (11.1 %), O···H (8.0 %) and N···H (0.4 %). The reaction mechanism for the formation of the β-lactam is also proposed. The three sets of compounds were evaluated for their antibacterial activity against three gram-positive (Pseudomonas aeruginosa, Bacillus subtilis and Staphylococcus aureus) and one gram-negative strain (Escherichia coli). The β2,3-amino acids 8a, 8b and 8h showed good antibacterial activity against all strains with MIC values between 0.17 and 1.44 mM, comparable to the standard ampicillin. All three compounds showed better activity to E. coli than ampicillin. Interestingly, molecular docking to the penicillin-binding protein (PBP 2X) showed the same three compounds 8a, 8b and 8h to have a better MolDock score than ampicillin and the free carboxyl groups in the β-amino acid to bind to Ser337, blocking it from further binding with peptidoglycan for cross-linking and subsequent transpeptidation.

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Acknowledgments

This research was supported by Grants from the National Research Foundation (NRF), South Africa, and was supported by the South African Research Chairs Initiative of the Department of Science and Technology. We thank Dr Mahesh Palkel for assisting with molecular docking studies.

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Authors and Affiliations

  1. School of Chemistry and Physics, University of KwaZulu-Natal, Private Bag X54001, Durban, 4001, South Africa

    Pramod Kadam, Bernard Omondi & Neil A. Koorbanally

  2. School of Pharmacy, University of KwaZulu-Natal, Private Bag X54001, Durban, 4001, South Africa

    Rajshekar Karpoormath

  3. School of Biological Sciences, University of KwaZulu-Natal, Private Bag X54001, Durban, 4001, South Africa

    Hafizah Chenia

  4. School of Engineering, University of KwaZulu-Natal, Durban, 4041, South Africa

    Deresh Ramjugernath

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  1. Pramod Kadam
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Correspondence to Neil A. Koorbanally.

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Kadam, P., Karpoormath, R., Omondi, B. et al. Stereo-selective synthesis, structural and antibacterial studies of novel glycosylated β2,3-amino acid analogues. Med Chem Res 24, 3174–3193 (2015). https://doi.org/10.1007/s00044-015-1370-4

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  • DOI: https://doi.org/10.1007/s00044-015-1370-4

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