Design, synthesis and biological evaluation of novel DNA gyrase inhibitors and their siderophore mimic conjugates.,Bioorganic Chemistry

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Design, synthesis and biological evaluation of novel DNA gyrase inhibitors and their siderophore mimic conjugates.
Bioorganic Chemistry ( IF 4.5 ) Pub Date : 2019-12-23 , DOI: 10.1016/j.bioorg.2019.103550
Andraž Lamut ₁ , Cristina D Cruz ₂ , Žiga Skok ₁ , Michaela Barančoková ₁ , Nace Zidar ₁ , Anamarija Zega ₁ , Lucija Peterlin Mašič ₁ , Janez Ilaš ₁ , Päivi Tammela ₂ , Danijel Kikelj ₁ , Tihomir Tomašič ₁

Affiliation

Bacterial DNA gyrase is an important target for the development of novel antibacterial drugs, which are urgently needed because of high level of antibiotic resistance worldwide. We designed and synthesized new 4,5,6,7-tetrahydrobenzo[d]thiazole-based DNA gyrase B inhibitors and their conjugates with siderophore mimics, which were introduced to increase the uptake of inhibitors into the bacterial cytoplasm. The most potent conjugate 34 had an IC50 of 58 nM against Escherichia coli DNA gyrase and displayed MIC of 14 µg/mL against E. coli ΔtolC strain. Only minor improvements in the antibacterial activities against wild-type E. coli in low-iron conditions were seen for DNA gyrase inhibitor - siderophore mimic conjugates.

中文翻译：

新型DNA促旋酶抑制剂及其铁载体模拟缀合物的设计，合成和生物学评估。

细菌DNA促旋酶是开发新型抗菌药物的重要目标，由于全球范围内对抗生素的高度耐药，迫切需要这种细菌。我们设计并合成了新的基于4,5,6,7-四氢苯并[d]噻唑的DNA促旋酶B抑制剂及其与铁载体模拟物的结合物，它们被引入以增加抑制剂对细菌细胞质的吸收。最有效的结合物34对大肠杆菌DNA促旋酶的IC50为58 nM，对大肠杆菌ΔtolC菌株的MIC为14 µg / mL。对于DNA促旋酶抑制剂-铁载体模拟缀合物，在低铁条件下对野生型大肠杆菌的抗菌活性仅获得了较小的改善。

更新日期：2019-12-23

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