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2,6-Difluorobenzamide Inhibitors of Bacterial Cell Division Protein FtsZ: Design, Synthesis, and Structure-Activity Relationships.
ChemMedChem. 2017 08 22; 12(16):1303-1318.C

Abstract

A wide variety of drug-resistant microorganisms are continuously emerging, restricting the therapeutic options for common bacterial infections. Antimicrobial agents that were originally potent are now no longer helpful, due to their weak or null activity toward these antibiotic-resistant bacteria. In addition, none of the recently approved antibiotics affect innovative targets, resulting in a need for novel drugs with innovative antibacterial mechanisms of action. The essential cell division protein filamentous temperature-sensitive Z (FtsZ) has emerged as a possible target, thanks to its ubiquitous expression and its homology to eukaryotic β-tubulin. In the latest years, several compounds were shown to interact with this prokaryotic protein and selectively inhibit bacterial cell division. Recently, our research group developed interesting derivatives displaying good antibacterial activities against methicillin-resistant Staphylococcus aureus, as well as vancomycin-resistant Enterococcus faecalis and Mycobacterium tuberculosis. The aim of the present study was to summarize the structure-activity relationships of differently substituted heterocycles, linked by a methylenoxy bridge to the 2,6-difluorobenzamide, and to validate FtsZ as the real target of this class of antimicrobials.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Straniero V
Department of Pharmaceutical Sciences, Università degli Studi di Milano, via Mangiagalli 25, 20133, Milano, Italy.
Zanotto C
Department of Medical Biotechnologies and Translational Medicine, Università degli Studi di Milano, via Vanvitelli 32, 20129, Milano, Italy.
Straniero L
Department of Biomedical Sciences, Humanitas University, via Manzoni 113, 2, 0089, Rozzano-Milano, Italy.
Casiraghi A
Department of Pharmaceutical Sciences, Università degli Studi di Milano, via Mangiagalli 25, 20133, Milano, Italy.
Duga S
Department of Biomedical Sciences, Humanitas University, via Manzoni 113, 2, 0089, Rozzano-Milano, Italy. Humanitas Clinical and Research Center, via Manzoni 56, 20089, Rozzano-Milano, Italy.
Radaelli A
Department of Pharmacological and Biomolecular Science, Università degli Studi di Milano, via Balzaretti 9, 20133, Milano, Italy. Cellular and Molecular Pharmacology Section, National Research Council (CNR), Institute of Neurosciences, Università degli Studi di Milano, via Vanvitelli 32, 20129, Milano, Italy.
De Giuli Morghen C
Catholic University "Our Lady of Good Counsel", Rr. Dritan Hoxha, Tirana, Albania.
Valoti E
Department of Pharmaceutical Sciences, Università degli Studi di Milano, via Mangiagalli 25, 20133, Milano, Italy.

MeSH

Anti-Bacterial AgentsBacteriaBacterial ProteinsBenzamidesCell LineCell SurvivalCytoskeletal ProteinsDrug DesignEnterococcus faecalisHumansMethicillin-Resistant Staphylococcus aureusMicrobial Sensitivity TestsMycobacterium tuberculosisStructure-Activity Relationship

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28586174

Citation

Straniero, Valentina, et al. "2,6-Difluorobenzamide Inhibitors of Bacterial Cell Division Protein FtsZ: Design, Synthesis, and Structure-Activity Relationships." ChemMedChem, vol. 12, no. 16, 2017, pp. 1303-1318.
Straniero V, Zanotto C, Straniero L, et al. 2,6-Difluorobenzamide Inhibitors of Bacterial Cell Division Protein FtsZ: Design, Synthesis, and Structure-Activity Relationships. ChemMedChem. 2017;12(16):1303-1318.
Straniero, V., Zanotto, C., Straniero, L., Casiraghi, A., Duga, S., Radaelli, A., De Giuli Morghen, C., & Valoti, E. (2017). 2,6-Difluorobenzamide Inhibitors of Bacterial Cell Division Protein FtsZ: Design, Synthesis, and Structure-Activity Relationships. ChemMedChem, 12(16), 1303-1318. https://doi.org/10.1002/cmdc.201700201
Straniero V, et al. 2,6-Difluorobenzamide Inhibitors of Bacterial Cell Division Protein FtsZ: Design, Synthesis, and Structure-Activity Relationships. ChemMedChem. 2017 08 22;12(16):1303-1318. PubMed PMID: 28586174.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 2,6-Difluorobenzamide Inhibitors of Bacterial Cell Division Protein FtsZ: Design, Synthesis, and Structure-Activity Relationships. AU - Straniero,Valentina, AU - Zanotto,Carlo, AU - Straniero,Letizia, AU - Casiraghi,Andrea, AU - Duga,Stefano, AU - Radaelli,Antonia, AU - De Giuli Morghen,Carlo, AU - Valoti,Ermanno, Y1 - 2017/07/11/ PY - 2017/03/31/received PY - 2017/05/30/revised PY - 2017/6/7/pubmed PY - 2017/10/11/medline PY - 2017/6/7/entrez KW - 2,6-difluorobenzamides KW - FtsZ KW - MRSA KW - antibiotics KW - antimicrobial resistance KW - inhibitors SP - 1303 EP - 1318 JF - ChemMedChem JO - ChemMedChem VL - 12 IS - 16 N2 - A wide variety of drug-resistant microorganisms are continuously emerging, restricting the therapeutic options for common bacterial infections. Antimicrobial agents that were originally potent are now no longer helpful, due to their weak or null activity toward these antibiotic-resistant bacteria. In addition, none of the recently approved antibiotics affect innovative targets, resulting in a need for novel drugs with innovative antibacterial mechanisms of action. The essential cell division protein filamentous temperature-sensitive Z (FtsZ) has emerged as a possible target, thanks to its ubiquitous expression and its homology to eukaryotic β-tubulin. In the latest years, several compounds were shown to interact with this prokaryotic protein and selectively inhibit bacterial cell division. Recently, our research group developed interesting derivatives displaying good antibacterial activities against methicillin-resistant Staphylococcus aureus, as well as vancomycin-resistant Enterococcus faecalis and Mycobacterium tuberculosis. The aim of the present study was to summarize the structure-activity relationships of differently substituted heterocycles, linked by a methylenoxy bridge to the 2,6-difluorobenzamide, and to validate FtsZ as the real target of this class of antimicrobials. SN - 1860-7187 UR - https://www.unboundmedicine.com/medline/citation/28586174/26_Difluorobenzamide_Inhibitors_of_Bacterial_Cell_Division_Protein_FtsZ:_Design_Synthesis_and_Structure_Activity_Relationships_ L2 - https://doi.org/10.1002/cmdc.201700201 DB - PRIME DP - Unbound Medicine ER -