Identification of active main metabolites of anti-infective inhibitors of the macrophage infectivity potentiator protein by liquid chromatography using mass detection.

Due to increasing antibiotic resistance, the development of anti-infectives with new mechanisms of action is crucial. Virulence factors such as the "macrophage infectivity potentiator" (Mip) protein, which catalyzes the folding of proline-containing proteins by means of their cis-trans isomerase (PPIase) activity, have come into focus as a potential new target. Since the inhibition of Mip by small molecules has been shown to lead to reduced virulence and survival in vitro, especially of Gram-negative bacteria such as Burkholderia pseudomallei (Bp), Neisseria meningitidis (Nm), and Neisseria gonorrhoeae (Ng), or Coxiella burnetii (Cb), among many others, a library of Mip inhibitors was developed. As drug metabolism has a significant impact on the overall therapeutic outcome, this report describes the biotransformation of the most potent Mip inhibitors. Therefore, the anti-infectives were treated using human liver microsomes in vitro. Liquid chromatography with tandem mass spectrometry (LC/MS-MS) methods were applied to identify the metabolites and quantify the metabolic degradation of the hit compounds. Active metabolites, N-oxides, were found, leading to new opportunities for further drug development.

Fluorine walk: The impact of fluorine in quinolone amides on their activity against African sleeping sickness.

Human African Trypanosomiasis, also known as African sleeping sickness, is caused by the parasitic protozoa of the genus Trypanosoma. If there is no pharmacological intervention, the parasites can cross the blood-brain barrier (BBB), inevitably leading to death of the patients. Previous investigation identified the quinolone amide GHQ168 as a promising lead compound having a nanomolar activity against T. b. brucei. Here, the role of a fluorine substitution at different positions was investigated in regard to toxicity, pharmacokinetics, and antitrypanosomal activity. This 'fluorine walk' led to new compounds with improved metabolic stability and consistent activity against T. b. brucei. The ability of the new quinolone amides to cross the BBB was confirmed using an 18F-labelled quinolone amide derivative by means of ex vivo autoradiography of a murine brain.