El-Shershaby Mohamed H, El-Gamal Kamal M, Bayoumi Ashraf H, El-Adl Khaled, Ahmed Hany E A, Abulkhair Hamada S
Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt.
Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt.
Arch Pharm (Weinheim). 2021 Feb;354(2):e2000277. doi: 10.1002/ardp.202000277. Epub 2020 Oct 20.
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 IC 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.
在此，我们报告了新型喹啉衍生物作为DNA回旋酶抑制剂的合成及体外抗菌评估。针对一组致病微生物评估了其初步抗菌活性，这些微生物包括革兰氏阳性菌（肺炎链球菌和枯草芽孢杆菌）、革兰氏阴性菌（铜绿假单胞菌和大肠杆菌）以及真菌菌株（烟曲霉、总状共头霉、白地霉和白色念珠菌）。对显示出最佳活性的化合物进行了进一步的生物学研究，以确定它们对所选病原体的最低抑菌浓度（MIC）以及它们对大肠杆菌DNA回旋酶的体外活性，以了解其抗菌作用是否通过抑制该酶介导。四种新衍生物（14、17、20和23）表现出相对较强的抗菌活性，MIC值在0.66 - 5.29μg/ml范围内。其中，化合物14对大多数测试的细菌和真菌菌株表现出特别强的广谱抗菌活性，MIC值在0.66 - 3.98μg/ml范围内。随后针对细菌DNA回旋酶靶酶的体外研究揭示了喹啉衍生物14具有显著的强抑制活性，这可以从其IC值（3.39μM）看出。此外，还对最具活性的化合物进行了分子对接研究，以探索新配体对作为其活性假定靶点的DNA回旋酶活性位点的结合亲和力。此外，还分析了最有效衍生物的ADMET特性，以评估它们作为良好药物候选物开发的潜力。
