Rational design, synthesis, molecular modeling, biological activity, and mechanism of action of polypharmacological norfloxacin hydroxamic acid derivatives
Journal article, 2023

Fluoroquinolones are broad-spectrum antibiotics that target gyrase and topoisomerase IV, involved in DNA compaction and segregation. We synthesized 28 novel norfloxacin hydroxamic acid derivatives with additional metal-chelating and hydrophobic pharmacophores, designed to enable interactions with additional drug targets. Several compounds showed equal or better activity than norfloxacin against Gram-positive, Gram-negative, and mycobacteria, with MICs as low as 0.18 mu M. The most interesting derivatives were selected for in silico, in vitro, and in vivo mode of action studies. Molecular docking, enzyme inhibition, and bacterial cytological profiling confirmed inhibition of gyrase and topoisomerase IV for all except two tested derivatives (10f and 11f). Further phenotypic analysis revealed polypharmacological effects on peptidoglycan synthesis for four derivatives (16a, 17a, 17b, 20b). Interestingly, compounds 17a, 17b, and 20b, showed never seen before effects on cell wall synthetic enzymes, including MreB, MurG, and PonA, suggesting a novel mechanism of action, possibly impairing the lipid II cycle. Addition of metal-chelating and lipophilic groups to norfloxacin yielded dual-action compounds inhibiting DNA gyrase/topoisomerase IV and bacterial cell wall synthesis.

Author

Ahmed M. Kamal El-sagheir

Assiut University

Ireny Abdelmesseh Nekhala Abdelmesseh

Chalmers, Life Sciences, Chemical Biology

Mohammed K. Abd El-Gaber

Assiut University

Ahmed S. Aboraia

Assiut University

Jonatan Norborg

Chalmers, Life Sciences, Chemical Biology

Ann-Britt Schäfer

Chalmers, Life Sciences, Chemical Biology

Michaela Wenzel

Chalmers, Life Sciences, Chemical Biology

Farghaly A. Omar

Assiut University

RSC Medicinal Chemistry

26328682 (ISSN)

Vol. 14 12 2593-2610

Subject Categories

Pharmacology and Toxicology

Medicinal Chemistry

Microbiology in the medical area

DOI

10.1039/d3md00309d

More information

Latest update

4/2/2024 1