Synthesis, antimicrobial evaluation, DNA gyrase inhibition, and in silico pharmacokinetic studies of novel quinoline derivatives

• Published in: Archiv der Pharmazie (Weinheim) 2021-02, Vol.354 (2), p.e2000277-n/a
• Main Authors: El‐Shershaby, Mohamed H., El‐Gamal, Kamal M., Bayoumi, Ashraf H., El‐Adl, Khaled, Ahmed, Hany E. A., Abulkhair, Hamada S.
• Format: Article
• Language: English
• Subjects: antimicrobial; Antimicrobial agents; Bacteria; Deoxyribonucleic acid; DNA; DNA gyrase; Enzymes; molecular docking; Pharmacokinetics; quinoline; Streptococcus infections; synthesis
• ISSN: 0365-6233; 1521-4184
• DOI: 10.1002/ardp.202000277

Herein, we report the synthesis and in vitro antimicrobial evaluation of novel quinoline derivatives as DNA gyrase inhibitors. The preliminary antimicrobial activity was assessed against a panel of pathogenic microbes including Gram‐positive bacteria (Streptococcus pneumoniae and Bacillus subtilis), Gram‐negative bacteria (Pseudomonas aeruginosa and Escherichia coli), and fungal strains (Aspergillus fumigatus, Syncephalastrum racemosum, Geotrichum candidum, and Candida albicans). Compounds that revealed the best activity were subjected to further biological studies to determine their minimum inhibitory concentrations (MICs) against the selected pathogens as well as their in vitro activity against the E. coli DNA gyrase, to realize whether their antimicrobial action is mediated via inhibition of this enzyme. Four of the new derivatives (14, 17, 20, and 23) demonstrated a relatively potent antimicrobial activity with MIC values in the range of 0.66–5.29 μg/ml. Among them, compound 14 exhibited a particularly potent broad‐spectrum antimicrobial activity against most of the tested strains of bacteria and fungi, with MIC values in the range of 0.66–3.98 μg/ml. A subsequent in vitro investigation against the bacterial DNA gyrase target enzyme revealed a significant potent inhibitory activity of quinoline derivative 14, which can be observed from its IC50 value (3.39 μM). Also, a molecular docking study of the most active compounds was carried out to explore the binding affinity of the new ligands toward the active site of DNA gyrase enzyme as a proposed target of their activity. Furthermore, the ADMET profiles of the most highly effective derivatives were analyzed to evaluate their potentials to be developed as good drug candidates. Novel quinoline derivatives were synthesized and evaluated for their antimicrobial activity as DNA gyrase inhibitors against a panel of pathogenic microbes including Gram‐positive (Streptococcus pneumoniae and Bacillus subtilis), Gram‐negative bacteria (Pseudomonas aeruginosa and Escherichia coli), and fungal strains (Aspergillus fumigatus, Syncephalastrum racemosum, Geotrichum candidum, and Candida albicans). A molecular docking study was carried out with the most active compounds to explore the binding affinity of the new ligands toward the active site of DNA gyrase.