Discovery and Optimization of Isoquinoline Ethyl Ureas as Antibacterial Agents

Our strategy to combat resistant bacteria consisted of targeting the GyrB/ParE ATP-binding sites located on bacterial DNA gyrase and topoisomerase IV and not utilized by marketed antibiotics. Screening around the minimal ethyl urea binding motif led to the identification of isoquinoline ethyl urea 13 as a promising starting point for fragment evolution. The optimization was guided by structure-based design and focused on antibacterial activity in vitro and in vivo, culminating in the discovery of unprecedented substituents able to interact with conserved residues within the ATP-binding site. A detailed characterization of the lead compound highlighted the potential for treatment of the problematic fluoroquinolone-resistant MRSA, VRE, and S. pneumoniae, and the possibility to offer patients an intravenous-to-oral switch therapy was supported by the identification of a suitable prodrug concept. Eventually, hERG K-channel block was identified as the main limitation of this chemical series, and efforts toward its minimization are reported.本研究针对耐药菌的防控策略，靶向细菌DNA促旋酶（DNA gyrase）与拓扑异构酶IV（topoisomerase IV）上的GyrB/ParE ATP结合位点（GyrB/ParE ATP-binding site）——此类位点未被现有上市抗生素所利用。通过围绕最小乙基脲结合基序（minimal ethyl urea binding motif）开展筛选，研究人员成功鉴定出异喹啉乙基脲13（isoquinoline ethyl urea 13），可作为片段进化（fragment evolution）的极具潜力的起始化合物。本次优化以基于结构的设计（structure-based design）为指导，重点围绕体外与体内抗菌活性展开，最终发现了可与ATP结合位点内保守残基（conserved residues）相互作用的全新取代基。对先导化合物（lead compound）的详细表征结果显示，其在治疗棘手的耐氟喹诺酮类耐甲氧西林金黄色葡萄球菌（fluoroquinolone-resistant MRSA）、耐万古霉素肠球菌（VRE）以及肺炎链球菌（S. pneumoniae）感染方面极具潜力；同时，研究人员鉴定出了合适的前药策略（prodrug concept），证实了可为患者提供静脉-口服转换治疗（intravenous-to-oral switch therapy）的可行性。最终，研究人员发现hERG钾离子通道（hERG K-channel）阻滞作用是该化学系列化合物的主要局限性，本文同时报道了为降低该副作用所开展的优化工作。