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The synthesis and biological evaluation of virtually designed fluoroquinolone analogs against fluoroquinolone-resistant Escherichia coli intended for UTI treatment
New Journal of Chemistry ( IF 2.7 ) Pub Date : 2020-07-13 , DOI: 10.1039/d0nj00657b Sakthivel Balasubramaniyan 1, 2, 3, 4, 5 , Navabshan Irfan 6, 7, 8, 9 , Chinnaiyan Senthilkumar 9, 10, 11 , Appavoo Umamaheswari 1, 2, 3, 4, 5 , Ayarivan Puratchikody 1, 2, 3, 4, 5
New Journal of Chemistry ( IF 2.7 ) Pub Date : 2020-07-13 , DOI: 10.1039/d0nj00657b Sakthivel Balasubramaniyan 1, 2, 3, 4, 5 , Navabshan Irfan 6, 7, 8, 9 , Chinnaiyan Senthilkumar 9, 10, 11 , Appavoo Umamaheswari 1, 2, 3, 4, 5 , Ayarivan Puratchikody 1, 2, 3, 4, 5
Affiliation
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Fluoroquinolones (FQs) are one of the most commonly prescribed classes of antibiotics for the treatment of urinary tract infections (UTIs), but FQ-resistant Escherichia coli (E. coli) in UTIs is widespread and increasing. In order to address the resistance-related issue, novel drug molecules with the capacity to overcome E. coli resistance are crucial for modern healthcare. Based on this rationale, the virtually screened novel FQ analogs FQ-49, FQ-70, FQ-131, FQ-132, FQ-137, FQ-147, FQ-151, FQ-172, FQ-177, and FQ-182 were synthesized using a microwave-assisted technique. These compounds possessed excellent activity against FQ-resistant E. coli and inhibited purified mutant DNA gyrase activity in vitro. A 3D-QSAR modeling study was used to identify the potent FQ analogs and calculate their molecular properties. Sequence analysis of the quinolone-resistance determining region (QRDR) of purified mutant DNA gyrase enzyme confirmed the presence of Ser83Leu and Asp87Asn mutations in FQ-resistant E. coli isolates from UTI patients. Overall, this study confirmed that ten of the synthesized novel FQ analogs exhibited extremely potent antibacterial activity against existing FQ-resistant E. coli, and they could be further successfully utilized for the treatment of UTIs.
中文翻译：
虚拟设计的氟喹诺酮类似物针对打算用于UTI治疗的抗氟喹诺酮类大肠杆菌的合成和生物学评估
氟喹诺酮类（FQs）是治疗尿路感染（UTIs）的最常用处方抗生素之一，但是UTI中耐FQ的大肠杆菌（E. coli）广泛存在并且正在增加。为了解决与耐药性有关的问题，具有克服大肠杆菌耐药性能力的新型药物分子对于现代医疗保健至关重要。基于此原理，虚拟筛选的新型FQ类似物FQ-49，FQ-70，FQ-131，FQ-132，FQ-137，FQ-147，FQ-151，FQ-172，FQ-177和FQ- 182使用微波辅助技术合成了它们。这些化合物具有优异的抗FQ大肠杆菌活性，并在体外抑制纯化的突变型DNA旋转酶活性。使用3D-QSAR建模研究来识别有效的FQ类似物并计算其分子性质。纯化的突变型DNA回旋酶的喹诺酮耐药性决定区（QRDR）的序列分析证实，来自UTI患者的FQ耐药大肠杆菌中存在Ser83Leu和Asp87Asn突变。总的来说，这项研究证实了十种合成的新型FQ类似物对现有的耐FQ大肠杆菌表现出极强的抗菌活性。，它们可以进一步成功地用于治疗UTI。
更新日期：2020-08-11
中文翻译：
虚拟设计的氟喹诺酮类似物针对打算用于UTI治疗的抗氟喹诺酮类大肠杆菌的合成和生物学评估
氟喹诺酮类（FQs）是治疗尿路感染（UTIs）的最常用处方抗生素之一，但是UTI中耐FQ的大肠杆菌（E. coli）广泛存在并且正在增加。为了解决与耐药性有关的问题，具有克服大肠杆菌耐药性能力的新型药物分子对于现代医疗保健至关重要。基于此原理，虚拟筛选的新型FQ类似物FQ-49，FQ-70，FQ-131，FQ-132，FQ-137，FQ-147，FQ-151，FQ-172，FQ-177和FQ- 182使用微波辅助技术合成了它们。这些化合物具有优异的抗FQ大肠杆菌活性，并在体外抑制纯化的突变型DNA旋转酶活性。使用3D-QSAR建模研究来识别有效的FQ类似物并计算其分子性质。纯化的突变型DNA回旋酶的喹诺酮耐药性决定区（QRDR）的序列分析证实，来自UTI患者的FQ耐药大肠杆菌中存在Ser83Leu和Asp87Asn突变。总的来说，这项研究证实了十种合成的新型FQ类似物对现有的耐FQ大肠杆菌表现出极强的抗菌活性。，它们可以进一步成功地用于治疗UTI。
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