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

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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.