Design, synthesis, molecular docking study, and antibacterial evaluation of some new fluoroquinolone analogues bearing a quinazolinone moiety

Abstract

Background Increasing bacterial resistance to quinolones is concerning. Hence, the development of novel quinolones by chemical modifications to overcome quinolone resistance is an attractive perspective in this context. Objective In this study, it is aimed to design and synthesize a novel series of functionalized fluoroquinolones using ciprofloxacin and sarafloxacin cores by hybridization of quinazolinone derivatives. This objective was tested by a comprehensive set of in vitro antibacterial assays in addition to SAR (structure-activity relationship) characterisation studies. Methods A nucleophilic reaction of ciprofloxacin and sarafloxacin with 2-(chloromethyl)quinazolin-4(3H)-one in the presence of NaHCO 3 in dimethylformamide (DMF) was performed to obtain the desired compounds 5a-j. Novel compounds were characterised by 1 H, 13 C-NMR and IR spectroscopy, MS and elemental analysis. In silico pharmacokinetics prediction assays and molecular docking studies were performed to explore the binding characteristics and interactions. Antibacterial activities of the novel compounds were evaluated by Broth microdilution, well diffusion and disc diffusion assays against three gram-positive (Methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus aureus and Enterococcus faecalis) and three gramnegative bacteria (Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli). ResultsThe compounds exhibited moderate to good activities against gram-positive bacteria and weak to moderate activities against gram-negative bacteria. Amongst all ciprofloxacin-derivatives, compound 5d was the most potent agent with high antibacterial activity against gram-positive bacteria, including MRSA and S. aureus ((minimum inhibitory concentration (MIC) = 16 nM for both), that is 60 times more potent than ciprofloxacin as parent drug. Compound 5i from sarafloxacinderivatives was the most potent compound against MRSA and S. aureus (MIC = 0.125 μM). Well diffusion and disk diffusion assay results demonstrated confirmatory outcomes for the quantitative broth microdilution assay. Molecular docking study results were in accordance with the results of antibacterial activity assays. ConclusionThe results of the current study demonstrated that the novel ciprofloxacin and sarafloxacin derivatives synthesized here have promising antibacterial activities. Particularly, compounds 5d and 5i have potential for wider antibacterial applications following further analysis.

Modification, Characterization of New Thiazolidinone and Oxazolidinone Derived from Levofloxacin and Evaluation of Anti-Oxidant

“…2.4 Synthesis of oxazolidine-4-one derivatives (6-8) [10,23] To a well-stirred mixture of chloroacetic acid (0.0013 mmol) and drops of Et3N as a catalyst, Schiff bases [3][4][5] (0.0013 mmol) in DMF (10 mL) were added. After 35 hours of refluxing, the mixture was put into freezing water to produce the final result.…”

“…After 35 hours of refluxing, the mixture was put into freezing water to produce the final result. The physical properties are listed in Table 2. 2.5 Synthesis of thiazolidine-4-one derivatives (9-11) [10,17,24] A mixture of Schiff bases [3][4][5] (0.0013 mmol) and an excess of 2-mercapto acetic acid (0.0026 mmol) in DMF was refluxed for 35 hours. The solvent was evaporated, and the residue was neutralized with 5% Na2CO3 solution to remove excess 2-mercapto acetic acid.…”

“…Schiff bases derivatives [3][4][5] are synthesized by the reaction of acid hydrazide derived from levofloxacin with substituted aromatic ketones in Me-OH as a solvent. The FT-IR spectra of compounds [3][4][5] shown disappearance of amine absorption bands of acid hydrazide, while appearance of new bands of azomethine (C=N) at (1639-1641) cm -1 , FTIR spectral data showed absorption at (C-H) aromatic bands at (3160-3043) cm -1 , ν (C=O) amide absorption bands at (1689-1658) cm -1 and (C=C) aromatic bands at (1575-1542) cm -1 spectrum.…”

“…As a result, many anticancer fluoroquinolones differ from clinical antibacterial fluoroquinolone in that they have nitrogen-containing rings on the 7-position and the 2-position, like piperazine. Additionally, alterations for the carboxylic group at the 3-position were not documented [2,3]. This group was modified with heterocyclic derivatives and showed higher antioxidants than vitamin C. The most frequent heteroatoms are (N, O, and sulfur S) [4,15].…”

The Search for New Antibacterial Agents among 1,2,3-Triazole Functionalized Ciprofloxacin and Norfloxacin Hybrids: Synthesis, Docking Studies, and Biological Activity Evaluation

“…According to the literature data, nitrogen in piperazine ring can be modified with such heterocyclic moieties as phenylthiazole [13], thiazolidine [14], quinazoline [15], thiadiazole [16,17], pyrimidine [18,19], dithienylethene [20], and 1,2,4-triazole [21]. Azole functionalized hybrids revealed promising levels of antibacterial activity [22], which led us to assume the effectiveness of 1,2,3-triazole moiety utilization for hybrid modification of fluoroquinolones.…”