Design, Synthesis, Molecular Modeling, Biological Activity, and Mechanism of Action of Novel Amino Acid Derivatives of Norfloxacin

Two series of N4-substituted piperazinyl amino acid derivatives of norfloxacin (24 new compounds) were designed and synthesized to attain structural surrogates with additional binding sites and enhanced antibacterial activity. Synthesized derivatives showed increased antibacterial and antimycobacterial activity compared to their lead structure, norfloxacin. Molecular modeling studies supported the notion that the derivatives can establish additional bonds with the target enzymes gyrase and topoisomerase IV. In vitro enzyme inhibition assays confirmed that the tested compounds were significant inhibitors of these enzymes. Inhibition of gyrase and topoisomerase IV was then confirmed in living bacterial cells using bacterial cytological profiling of both Gram-negative Escherichia coli and Gram-positive Bacillus subtilis, revealing a typical topoisomerase inhibition phenotype characterized by severe nucleoid packing defects. Several derivatives exhibited additional effects on the Gram-positive cell wall synthesis machinery and/or the cytoplasmic membrane, which likely contributed to their increased antibacterial activity. While we could not identify specific cell wall or membrane targets, membrane depolarization was not observed. Our experiments further suggest that cell wall synthesis inhibition most likely occurs outside the membrane-bound lipid II cycle.

Abdelmesseh, Ireny Abdelmesseh Nekhala,1993Chalmers tekniska högskola,Chalmers University of Technology(Swepub:cth)ireny (författare)
Abd El-Gaber, Mohammed K.Assiut University (författare)
Aboraia, Ahmed S.Assiut University (författare)
Persson, Jonatan (författare)
Schäfer, Ann-Britt,1993Chalmers tekniska högskola,Chalmers University of Technology(Swepub:cth)annscha (författare)
Wenzel, Michaela,1986Chalmers tekniska högskola,Chalmers University of Technology(Swepub:cth)wenzelm (författare)
Omar, Farghaly A.Assiut University (författare)
Assiut UniversityChalmers tekniska högskola (creator_code:org_t)

Av författaren/redakt...: El-sagheir, Ahme ...; Abdelmesseh, Ire ...; Abd El-Gaber, Mo ...; Aboraia, Ahmed S ...; Persson, Jonatan; Schäfer, Ann-Bri ...; visa fler...; Wenzel, Michaela ...; Omar, Farghaly A ...; visa färre...

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