Enzymatically triggered CO-releasing molecules as potential anti-malarial and anti-bacterial compounds

虽然一氧化碳（CO）是一种有毒的空气污染物，但酶促过程存在于包括人类在内的高等生物体中，其内源性产生CO作为一种重要的信号分子。例如，CO已被证明表现出强烈的抗炎和细胞保护作用。虽然CO的大部分生理效应的分子机制仍有待详细建立，但大量数据已经证明了CO在人类医学治疗应用中的巨大潜力。为了克服与通过吸入气体的CO给药相关的风险和毒副作用，CO释放分子（CORM）的开发已经成为重要的研究领域。在这种情况下，由申请人之一引入的铁基酶触发的CORM（ET-CORMS）打开了特别有希望的选择。在这里，我们建议开发新的ET-CORM，其被设计为用于治疗疟疾（和细菌感染，分别）和伴随的炎症过程的抗感染剂。其概念是制备双功能化合物，其中ET-CORM单元（酰氧基-环己二烯-Fe（CO）3络合物）与已建立的药效团缀合。第一个项目部分的重点是类似物的抗疟疾药物氯喹和ferroquine，分别含有酯酶激活的ET-CORM子结构。第二个项目部分旨在开发β-内酰胺抗生素的ET-CORM结合物（例如，衍生自6-氨基青霉酸），其由β-内酰胺酶触发，因此应对耐药细菌特别有效。该项目还涉及新方法的开发，例如关于非外消旋形式的平面手性酰氧基-环己二烯-Fe（CO）3络合物的合成。

While carbon monoxide (CO) is known as a toxic air pollutant, enzymatic processes exist in higher organisms, including humans, which generate CO endogenously as an essential signaling molecule. For instance, CO has been shown to exhibit strong anti-inflammatory and cyto-protective effects. While the molecular mechanisms of most of the physiological effects of CO remain to be established in detail, a wealth of data already demonstrates the great potential of CO for therapeutic applications in human medicine. To overcome the risks and toxic side effects linked to CO administration by inhalation of the gas, the development of CO-releasing molecules (CORMs) has become an important field of research. In this context, the iron-based enzyme-triggered CORMs (ET-CORMS) introduced by one of the applicants open particularly promising options. Here, we propose the development of new ET-CORMs, which are designed as anti-infective agents for the treatment of malaria (and bacterial infections, respectively) and the accompanying inflammatory processes. The concept is to prepare bifunctional compounds, in which an ET-CORM unit (an acyloxy-cyclohexadiene-Fe(CO)3 complex) is conjugated to an established pharmacophor. The first project part focuses on analogs of the anti-malarial drugs chloroquine and ferroquine, respectively, containing an esterase-activated ET-CORM substructure. A second project part aims at the development of ET-CORM conjugates of beta-lactam antibiotics (e.g. derived from 6-aminopenicillic acid), which are triggered by beta-lactamases and therefore should be particularly active against resistant bacteria. The project also involves the development of new methodology, for instance concerning the synthesis of the planar chiral acyloxy-cyclohexadiene-Fe(CO)3 complexes in non racemic form.