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

虽然一氧化碳(CO)被认为是一种有毒的空气污染物，但在包括人类在内的高等生物体中存在着酶的过程，它作为一种重要的信号分子在内源性地产生一氧化碳。例如，一氧化碳已被证明具有强大的抗炎和细胞保护作用。虽然一氧化碳的大部分生理作用的分子机制尚不清楚，但大量的数据已经证明了一氧化碳在人类医学治疗应用中的巨大潜力。为了克服吸入CO带来的风险和毒副作用，开发CO释放分子已成为一个重要的研究领域。在这种情况下，申请者之一介绍的铁基酶触发球茎(ET-球茎)打开了特别有希望的选择。在这里，我们建议开发新的ET球茎，它被设计为治疗疟疾(和细菌感染)和伴随的炎症过程的抗感染药物。其概念是制备双功能化合物，其中ET-球茎单元(酰氧基环己二烯-Fe(CO)3络合物)连接到已建立的药效团。第一个项目部分集中于抗疟疾药物氯喹和铁喹的类似物，分别含有酯酶激活的ET-球茎亚结构。第二个项目部分旨在开发β-内酰胺类抗生素的ET-球茎结合物(例如来自6-氨基青霉酸)，这种抗生素由β-内酰胺酶触发，因此对耐药细菌应特别有效。该项目还涉及开发新的方法学，例如关于以非外消旋形式合成平面手性酰氧基环己二烯-Fe(CO)3络合物。

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.