一些带有喹唑啉酮部分的新型氟喹诺酮类似物的设计、合成、分子对接研究和抗菌评价,DARU Journal of Pharmaceutical Sciences

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一些带有喹唑啉酮部分的新型氟喹诺酮类似物的设计、合成、分子对接研究和抗菌评价
DARU Journal of Pharmaceutical Sciences ( IF 2.5 ) Pub Date : 2020-10-08 , DOI: 10.1007/s40199-020-00373-6
Maryam Norouzbahari ₁ , Somayeh Salarinejad ₂ , Mümtaz Güran ₁ , Gizem Şanlıtürk _{1,

3} , Zahra Emamgholipour ₂ , Hamid Reza Bijanzadeh ₄ , Mahsa Toolabi ₅ , Alireza Foroumadi _{2,

6}

Affiliation

背景技术增加细菌对喹诺酮类药物的耐药性令人担忧。因此，在这种情况下，通过化学修饰开发新型喹诺酮以克服喹诺酮耐药性是一个有吸引力的前景。目的在本研究中，旨在通过喹唑啉酮衍生物的杂交，使用环丙沙星和沙拉沙星核心设计和合成一系列新型功能化氟喹诺酮类药物。除了 SAR（结构-活性关系）表征研究外，该目标还通过一套全面的体外抗菌试验进行了测试。方法在二甲基甲酰胺 (DMF) 中，在 NaHCO3 存在下，进行环丙沙星和沙拉沙星与 2-(氯甲基)喹唑啉-4(3H)-one 的亲核反应，以获得所需的化合物 5a-j。新化合物的特征在于 1H，13C-NMR和IR光谱、MS和元素分析。进行了计算机药代动力学预测分析和分子对接研究，以探索结合特征和相互作用。通过肉汤微量稀释、孔扩散和圆盘扩散试验对三种革兰氏阳性菌（耐甲氧西林金黄色葡萄球菌 (MRSA)、金黄色葡萄球菌和粪肠球菌）和三种革兰氏阴性菌（铜绿假单胞菌、克雷伯氏菌）的抗菌活性进行了评估肺炎链球菌、大肠杆菌）。结果化合物对革兰氏阳性菌表现出中等至良好的活性，对革兰氏阴性菌表现出弱至中等的活性。在所有环丙沙星衍生物中，化合物 5d 是对革兰氏阳性菌具有高抗菌活性的最强药物，来自沙拉沙星衍生物的化合物 5i 是对抗 MRSA 和金黄色葡萄球菌的最有效化合物（MIC = 0.125 μM）。孔扩散和圆盘扩散试验结果证明了定量肉汤微量稀释试验的确认结果。分子对接研究结果与抗菌活性测定结果一致。结论目前的研究结果表明，这里合成的新型环丙沙星和沙拉沙星衍生物具有良好的抗菌活性。特别是，化合物 5d 和 5i 在进一步分析后具有更广泛的抗菌应用潜力。来自沙拉沙星衍生物的化合物 5i 是对抗 MRSA 和金黄色葡萄球菌的最有效化合物（MIC = 0.125 μM）。孔扩散和圆盘扩散试验结果证明了定量肉汤微量稀释试验的确认结果。分子对接研究结果与抗菌活性测定结果一致。结论目前的研究结果表明，这里合成的新型环丙沙星和沙拉沙星衍生物具有良好的抗菌活性。特别是，化合物 5d 和 5i 在进一步分析后具有更广泛的抗菌应用潜力。孔扩散和圆盘扩散试验结果证明了定量肉汤微量稀释试验的确认结果。分子对接研究结果与抗菌活性测定结果一致。结论目前的研究结果表明，这里合成的新型环丙沙星和沙拉沙星衍生物具有良好的抗菌活性。特别是，化合物 5d 和 5i 在进一步分析后具有更广泛的抗菌应用潜力。孔扩散和圆盘扩散试验结果证明了定量肉汤微量稀释试验的确认结果。分子对接研究结果与抗菌活性测定结果一致。结论目前的研究结果表明，这里合成的新型环丙沙星和沙拉沙星衍生物具有良好的抗菌活性。特别是，经过进一步分析，化合物 5d 和 5i 具有更广泛的抗菌应用潜力。

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

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 NaHCO3 in dimethylformamide (DMF) was performed to obtain the desired compounds 5a-j. Novel compounds were characterised by 1H, 13C- 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 gram-negative bacteria (Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli). RESULTS The 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 sarafloxacin-derivatives 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. CONCLUSION The 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.

更新日期：2020-10-08

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