• Benzamidobenzoic acids as potent PqsD inhibitors for the treatment of Pseudomonas aeruginosa infections.

      Hinsberger, Stefan; de Jong, Johannes C; Groh, Matthias; Haupenthal, Jörg; Hartmann, Rolf W (2014-04-09)
      Targeting PqsD is a promising novel approach to disrupt bacterial cell-to-cell-communication in Pseudomonas aeruginosa. In search of selective PqsD inhibitors, two series of benzamidobenzoic acids - one published as RNAP inhibitors and the other as PqsD inhibitors - were investigated for inhibitory activity toward the respective other enzyme. Additionally, novel derivatives were synthesized and biologically evaluated. By this means, the structural features needed for benzamidobenzoic acids to be potent and, most notably, selective PqsD inhibitors were identified. The most interesting compound of this study was the 3-Cl substituted compound 5 which strongly inhibits PqsD (IC₅₀ 6.2 μM) while exhibiting no inhibition of RNAP.
    • Expanding the scaffold for bacterial RNA polymerase inhibitors: design, synthesis and structure–activity relationships of ureido-heterocyclic-carboxylic acids

      Elgaher, Walid A. M.; Fruth, Martina; Groh, Matthias; Haupenthal, Jörg; Hartmann, Rolf W.; Department of Drug Design and Optimization, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Campus C2.3, Saarland University, 66123 Saarbrücken, Germany (2014-01-22)
    • Exploring the chemical space of ureidothiophene-2-carboxylic acids as inhibitors of the quorum sensing enzyme PqsD from Pseudomonas aeruginosa.

      Sahner, J Henning; Empting, Martin; Kamal, Ahmed; Weidel, Elisabeth; Groh, Matthias; Börger, Carsten; Hartmann, Rolf W; Pharmaceutical and Medicinal Chemistry, Saarland University & Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Department of Drug Design and Optimization, Campus C2 3, 66123 Saarbrücken, Germany. (2015-05-26)
      Pseudomonas aeruginosa employs a quorum sensing (QS) communication system that makes use of small diffusible molecules. Among other effects, the QS system coordinates the formation of biofilm which decisively contributes to difficulties in the therapy of Pseudomonas infections. The present work deals with the structure-activity exploration of ureidothiophene-2-carboxylic acids as inhibitors of PqsD, a key enzyme in the biosynthetic pathway of signal molecules in the Pseudomonas QS system. We describe an improvement of the inhibitory activity by successfully combining features from two different PqsD inhibitor classes. Furthermore the functional groups, which are responsible for the inhibitory potency, were identified. Moreover, the inability of the new inhibitors, to prevent signal molecule formation in whole cell assays, is discussed.
    • New insights into the bacterial RNA polymerase inhibitor CBR703 as a starting point for optimization as an anti-infective agent.

      Zhu, Weixing; Haupenthal, Jörg; Groh, Matthias; Fountain, Michelle; Hartmann, Rolf W (2014-07)
      CBR703 was reported to inhibit bacterial RNA polymerase (RNAP) and biofilm formation, considering it to be a good candidate for further optimization. While synthesized derivatives of CBR703 did not result in more-active RNAP inhibitors, we observed promising antibacterial activities. These again correlated with a significant cytotoxicity toward mammalian cells. Furthermore, we suspect the promising effects on biofilm formation to be artifacts. Consequently, this class of compounds can be considered unattractive as antibacterial agents.