• Design and Synthesis of Bioisosteres of Acylhydrazones as Stable Inhibitors of the Aspartic Protease Endothiapepsin.

      Jumde, Varsha R; Mondal, Milon; Gierse, Robin M; Unver, M Yagiz; Magari, Francesca; van Lier, Roos C W; Heine, Andreas; Klebe, Gerhard; Hirsch, Anna K H; HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany. (Elsevier, 2018-11-06)
      Acylhydrazone-based dynamic combinatorial chemistry (DCC) is a powerful strategy for the rapid identification of novel hits. Even though acylhydrazones are important structural motifs in medicinal chemistry, their further progression in development may be hampered by major instability and potential toxicity under physiological conditions. It is therefore of paramount importance to identify stable replacements for acylhydrazone linkers. Herein, we present the first report on the design and synthesis of stable bioisosteres of acylhydrazone-based inhibitors of the aspartic protease endothiapepsin as a follow-up to a DCC study. The most successful bioisostere is equipotent, bears an amide linker, and we confirmed its binding mode by X-ray crystallography. Having some validated bioisosteres of acylhydrazones readily available might accelerate hit-to-lead optimization in future acylhydrazone-based DCC projects.
    • Pathoblockers or antivirulence drugs as a new option for the treatment of bacterial infections

      Calvert, Matthew B; Jumde, Varsha R; Titz, Alexander
      The rapid development of antimicrobial resistance is threatening mankind to such an extent that the World Health Organization expects more deaths from infections than from cancer in 2050 if current trends continue. To avoid this scenario, new classes of anti-infectives must urgently be developed. Antibiotics with new modes of action are needed, but other concepts are also currently being pursued. Targeting bacterial virulence as a means of blocking pathogenicity is a promising new strategy for disarming pathogens. Furthermore, it is believed that this new approach is less susceptible towards resistance development. In this review, recent examples of anti-infective compounds acting on several types of bacterial targets, e.g., adhesins, toxins and bacterial communication, are described.
    • Potential Dental Biofilm Inhibitors: Dynamic Combinatorial Chemistry Affords Sugar-Based Molecules that Target Bacterial Glucosyltransferase.

      Hartman, Alwin M; Jumde, Varsha R; Elgaher, Walid A M; Te Poele, Evelien M; Dijkhuizen, Lubbert; Hirsch, Anna K H; HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany. (Wiley-VCH, 2020-06-16)
      We applied dynamic combinatorial chemistry (DCC) to find novel ligands of the bacterial virulence factor glucosyltransferase (GTF) 180. GTFs are the major producers of extracellular polysaccharides, which are important factors in the initiation and development of cariogenic dental biofilms. Following a structure-based strategy, we designed a series of 36 glucose- and maltose-based acylhydrazones as substrate mimics. Synthesis of the required mono- and disaccharide-based aldehydes set the stage for DCC experiments. Analysis of the dynamic combinatorial libraries (DCLs) by UPLC-MS revealed major amplification of four compounds in the presence of GTF180. Moreover, we found that derivatives of the glucose-acceptor maltose at the C1-hydroxy group act as glucose-donors and are cleaved by GTF180. The synthesized hits display medium to low binding affinity (KD values of 0.4-10.0 mm) according to surface plasmon resonance. In addition, they were investigated for inhibitory activity in GTF-activity assays. The early-stage DCC study reveals that careful design of DCLs opens up easy access to a broad class of novel compounds that can be developed further as potential inhibitors.
    • Rapid Discovery of Aspartyl Protease Inhibitors Using an Anchoring Approach.

      Konstantinidou, Markella; Magari, Francesca; Sutanto, Fandi; Haupenthal, Jörg; Jumde, Varsha R; Ünver, M Yagiz; Heine, Andreas; Camacho, Carlos Jamie; Hirsch, Anna K H; Klebe, Gerhard; et al. (Wiley-VCH, 2020-03-18)
      Pharmacophore searches that include anchors, fragments contributing above average to receptor binding, combined with one-step syntheses are a powerful approach for the fast discovery of novel bioactive molecules. Here, we are presenting a pipeline for the rapid and efficient discovery of aspartyl protease inhibitors. First, we hypothesized that hydrazine could be a multi-valent warhead to interact with the active site Asp carboxylic acids. We incorporated the hydrazine anchor in a multicomponent reaction and created a large virtual library of hydrazine derivatives synthetically accessible in one-step. Next, we performed anchor-based pharmacophore screening of the libraries and resynthesized top-ranked compounds. The inhibitory potency of the molecules was finally assessed by an enzyme activity assay and the binding mode confirmed by several soaked crystal structures supporting the validity of the hypothesis and approach. The herein reported pipeline of tools will be of general value for the rapid generation of receptor binders beyond Asp proteases.