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Maurer C.K.,Helmholtz Institute for Pharmaceutical Research Saarland HIPS | Steinbach A.,Helmholtz Institute for Pharmaceutical Research Saarland HIPS | Hartmann R.W.,Helmholtz Institute for Pharmaceutical Research Saarland HIPS | Hartmann R.W.,Saarland University
Journal of Pharmaceutical and Biomedical Analysis | Year: 2013

The appearance of antibiotic resistance requires novel therapeutic strategies. One approach is to selectively attenuate bacterial pathogenicity by interfering with bacterial cell-to-cell communication known as quorum sensing. The PQS quorum sensing system of Pseudomonas aeruginosa employs as signal molecule the Pseudomonas Quinolone Signal (PQS; 2-heptyl-3-hydroxy-4-(1. H)-quinolone), a key contributor to virulence and biofilm formation. Thus, interference with PQS production is considered as promising approach for the development of novel anti-infectives. Therefore, in this study, we developed and validated an ultra-high performance liquid chromatographic-tandem mass spectrometric approach for reliable quantification of PQS in P. aeruginosa cultures for activity determination of new quorum sensing inhibitors. The poor chromatographic properties of PQS reported by others could be overcome by fast microwave-assisted acetylation. The validation procedure including matrix effects, recovery, process efficiency, selectivity, carry-over, accuracy and precision, stability of the processed sample, and limit of quantification demonstrated that the method fulfilled all requirements of common validation guidelines. Its applicability was successfully proven in routine testing. In addition, two-point calibration was shown to be applicable for fast and reliable PQS quantification saving time and resources. In summary, the described method provides a powerful tool for the discovery of new quorum sensing inhibitors as potential anti-infectives and illustrated the usefulness of chemical derivatization, acetylation, in liquid chromatography-mass spectrometry analysis. © 2013 Elsevier B.V.

Titz A.,Helmholtz Institute for Pharmaceutical Research Saarland HIPS
Topics in Medicinal Chemistry | Year: 2014

The Gram-negative bacterium Pseudomonas aeruginosa can establish life-threatening chronic infections through biofilm formation. The two bacterial lectins LecA and LecB play important roles in the formation of these biofilms and the inhibition of the lectins with carbohydrate-based ligands was shown to disrupt biofilms. These effects provide a novel therapeutic option against infections caused by P. aeruginosa. In addition to the urgent need for novel therapeutics against Pseudomonas infections, two major advantages arise from these lectins as targets for therapy: (1) the extracellular localization and site of activity of LecA and LecB circumvent the bacterial cell envelope as a particularly impermeable barrier of Gram-negative pathogens, which must be overcome by drugs against intracellular targets, and (2) the lectins are targets of the so-called anti-virulence therapy and therefore a reduced appearance of resistances towards lectin-directed drugs can be anticipated. In this review, the recent development of carbohydrate-based inhibitors against both lectins is summarized with a main focus on small molecules. © Springer-Verlag Berlin Heidelberg 2014.

Al-Soud Y.A.,Saarland University | Al-Soud Y.A.,Al al-Bayt University | Heydel M.,Saarland University | Hartmann R.W.,Saarland University | Hartmann R.W.,Helmholtz Institute for Pharmaceutical Research Saarland HIPS
Tetrahedron Letters | Year: 2011

A series of 1,3,5-trisubstituted 1,2,4-triazoles was designed and synthesized as potential inhibitors of ste-roidogenic CYP enzymes. The 1,2,4-triazole is part of the core structure fixing the geometry of the substances. A pyridine moiety was introduced as heme-binder. The target compounds were synthesized in two to four steps using silver carbonate mediated ring closure and Suzuki cross coupling reaction as key synthetic transformations. Biological testing of the synthesized compounds for the inhibition of the most important steroidogenic CYPs revealed compounds 29a and 30 as moderate inhibitors of aldo-sterone synthase (CYP11B2). © 2011 Elsevier Ltd. All rights reserved.

Lucas S.,Saarland University | Negri M.,Saarland University | Heim R.,Saarland University | Zimmer C.,Saarland University | And 2 more authors.
Journal of Medicinal Chemistry | Year: 2011

Pyridine substituted 3,4-dihydro-1H-quinolin-2-ones (e.g., 1-3) constitute a class of highly potent and selective inhibitors of aldosterone synthase (CYP11B2), a promising target for the treatment of hyperaldosteronism, congestive heart failure, and myocardial fibrosis. Among these, ethyl-substituted 3 possesses high selectivity against CYP1A2. Rigidification of 3 by incorporation of the ethyl group into a 5- or 6-membered ring affords compounds with a pyrroloquinolinone or pyridoquinolinone molecular scaffold (e.g., 4 and 5). It was found that these molecules are even more potent and selective CYP11B2 inhibitors than their corresponding open-chain analogues. Moreover, pyrroloquinolinone 4 exhibits no inhibition of the six most important hepatic CYP enzymes as well as a bioavailability in the range of the marketed drug fadrozole. The SAR studies disclose that subtle changes in the heterocyclic moiety are responsible for either a strong or a weak inhibition of the highly homologous 11-hydroxylase (CYP11B1). These results are not only important for fine-tuning the selectivity of CYP11B2 inhibitors but also for the development of selective CYP11B1 inhibitors that are of interest for the treatment of Cushing's syndrome and metabolic syndrome. © 2011 American Chemical Society.

Krug S.J.,Saarland University | Hu Q.,Saarland University | Hartmann R.W.,Saarland University | Hartmann R.W.,Helmholtz Institute for Pharmaceutical Research Saarland HIPS
Journal of Steroid Biochemistry and Molecular Biology | Year: 2013

A screening of structurally different steroid hormone synthesis inhibitors was performed in order to find a starting point for the development of a new inhibitor of the bifunctional steroidogenic enzyme CYP17A1. Emphasis was placed on determination of selectivity between the two catalytic steps, namely 17α-hydroxylase and C17,20-lyase. For that purpose a new inhibition assay has been developed. Hits identified within this novel assay demonstrated selective inhibition of CYP17A1 lyase activity, and thus mark the basis for the development of selective C17,20-lyase inhibitors for the treatment of prostate cancer. © 2012 Elsevier Ltd.

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