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Discovery of 4,5,6,7-Tetrahydrobenzo[1,2-d]thiazoles as Novel DNA Gyrase Inhibitors Targeting the ATP-Binding Site
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2015-07-08 00:00:00 , DOI: 10.1021/acs.jmedchem.5b00489 Tihomir Tomašič 1 , Sotirios Katsamakas 1, 2 , Žiga Hodnik 1 , Janez Ilaš 1 , Matjaž Brvar 3 , Tom Solmajer 3 , Sofia Montalvão 4 , Päivi Tammela 4 , Mihailo Banjanac 5 , Gabrijela Ergović 5 , Marko Anderluh 1 , Lucija Peterlin Mašič 1 , Danijel Kikelj 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2015-07-08 00:00:00 , DOI: 10.1021/acs.jmedchem.5b00489 Tihomir Tomašič 1 , Sotirios Katsamakas 1, 2 , Žiga Hodnik 1 , Janez Ilaš 1 , Matjaž Brvar 3 , Tom Solmajer 3 , Sofia Montalvão 4 , Päivi Tammela 4 , Mihailo Banjanac 5 , Gabrijela Ergović 5 , Marko Anderluh 1 , Lucija Peterlin Mašič 1 , Danijel Kikelj 1
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Bacterial DNA gyrase and topoisomerase IV are essential enzymes that control the topological state of DNA during replication and validated antibacterial drug targets. Starting from a library of marine alkaloid oroidin analogues, we identified low micromolar inhibitors of Escherichia coli DNA gyrase based on the 5,6,7,8-tetrahydroquinazoline and 4,5,6,7-tetrahydrobenzo[1,2-d]thiazole scaffolds. Structure-based optimization of the initial hits resulted in low nanomolar E. coli DNA gyrase inhibitors, some of which exhibited micromolar inhibition of E. coli topoisomerase IV and of Staphylococcus aureus homologues. Some of the compounds possessed modest antibacterial activity against Gram positive bacterial strains, while their evaluation against wild-type, impA and ΔtolCE. coli strains suggests that they are efflux pump substrates and/or do not possess the physicochemical properties necessary for cell wall penetration. Our study provides a rationale for optimization of this class of compounds toward balanced dual DNA gyrase and topoisomerase IV inhibitors with antibacterial activity.
中文翻译：
4,5,6,7-四氢苯并[1,2- d ]噻唑类化合物作为靶向ATP结合位点的新型DNA促旋酶抑制剂的发现
细菌DNA促旋酶和拓扑异构酶IV是必需的酶，可控制复制过程中DNA的拓扑状态和经过验证的抗菌药物靶标。从海洋生物碱类固醇激素类似物的库开始，我们基于5,6,7,8-四氢喹唑啉和4,5,6,7-四氢苯并[1,2- d ]噻唑确定了大肠杆菌DNA促旋酶的低微摩尔抑制剂脚手架。基于结构的最优化初始敲击产生了低纳摩尔浓度的大肠杆菌DNA促旋酶抑制剂，其中有些表现出对大肠杆菌拓扑异构酶IV和金黄色葡萄球菌的微摩尔抑制作用同源物。一些化合物对革兰氏阳性细菌菌株具有适度的抗菌活性，而对野生型，impA和ΔtolC大肠杆菌菌株的评估表明，它们是外排泵底物和/或不具有细胞壁必需的理化特性。渗透。我们的研究为针对具有抗菌活性的平衡双DNA促旋酶和拓扑异构酶IV抑制剂优化此类化合物提供了理论依据。
更新日期：2015-07-08
中文翻译：
4,5,6,7-四氢苯并[1,2- d ]噻唑类化合物作为靶向ATP结合位点的新型DNA促旋酶抑制剂的发现
细菌DNA促旋酶和拓扑异构酶IV是必需的酶，可控制复制过程中DNA的拓扑状态和经过验证的抗菌药物靶标。从海洋生物碱类固醇激素类似物的库开始，我们基于5,6,7,8-四氢喹唑啉和4,5,6,7-四氢苯并[1,2- d ]噻唑确定了大肠杆菌DNA促旋酶的低微摩尔抑制剂脚手架。基于结构的最优化初始敲击产生了低纳摩尔浓度的大肠杆菌DNA促旋酶抑制剂，其中有些表现出对大肠杆菌拓扑异构酶IV和金黄色葡萄球菌的微摩尔抑制作用同源物。一些化合物对革兰氏阳性细菌菌株具有适度的抗菌活性，而对野生型，impA和ΔtolC大肠杆菌菌株的评估表明，它们是外排泵底物和/或不具有细胞壁必需的理化特性。渗透。我们的研究为针对具有抗菌活性的平衡双DNA促旋酶和拓扑异构酶IV抑制剂优化此类化合物提供了理论依据。
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