Rok Frlan

Design and Synthesis of Novel N-Benzylidenesulfonohydrazide Inhibitors of MurC and MurD as Potential Antibacterial Agents

A series of novel N-benzylidenesulfonohydrazide compounds were designed and synthesized as inhibitors of UDP-N-acetylmuramic acid:L-alanine ligase (MurC) and UDP-N-acetylmuramoyl-L-alanine:D-glutamate ligase (MurD) from E. coli, involved in the biosynthesis of bacterial cell-walls. Some compounds possessed inhibitory activity against both enzymes with IC50 values as low as 30 μM. In addition, a new, one-pot synthesis of amidobenzaldehydes is reported.

Cobalt-Catalyzed Cross-Coupling of Grignards with Allylic and Vinylic Bromides: Use of Sarcosine as a Natural Ligand.

Sarcosine was discovered to be an excellent ligand for cobalt-catalyzed carbon-carbon cross-coupling of Grignard reagents with allylic and vinylic bromides. The Co(II)/sarcosine catalytic system is shown to perform efficiently when phenyl and benzyl Grignards are coupled with alkenyl bromides. Notably, previously unachievable Co-catalyzed coupling of allylic bromides with Grignards to linearly coupled α-products was also realized with Co(II)/sarcosine catalyst. This method was used for efficient preparation of the key intermediate in an alternative synthesis of the antihyperglycemic drug sitagliptin.

Design, Synthesis, and Evaluation of Novel Tyrosine‐Based DNA Gyrase B Inhibitors

The discovery and synthesis of new tyrosine‐based inhibitors of DNA gyrase B (GyrB), which target its ATPase subunit, is reported. Twenty‐four compounds were synthesized and evaluated for activity against DNA gyrase and DNA topoisomerase IV. The antibacterial properties of selected GyrB inhibitors were demonstrated by their activity against Staphylococcus aureus and Enterococcus faecalis in the low micromolar range. The most promising compounds, 8a and 13e, inhibited Escherichia coli and S. aureus GyrB with IC50 values of 40 and 30 µM. The same compound also inhibited the growth of S. aureus and E. faecalis with minimal inhibitory concentrations (MIC90) of 14 and 28 µg/mL, respectively.

Discovery of D-amino acid oxidase inhibitors based on virtual screening against the lid-open enzyme conformation

d-Amino acid oxidase (DAAO) inhibitors are typically small polar compounds with often suboptimal pharmacokinetic properties. Features of the native binding site limit the operational freedom of further medicinal chemistry efforts. We therefore initiated a structure based virtual screening campaign based on the X-ray structures of DAAO complexes where larger ligands shifted the loop (lid opening) covering the native binding site. The virtual screening of our in-house collection followed by the in vitro test of the best ranked compounds led to the identification of a new scaffold with micromolar IC50. Subsequent SAR explorations enabled us to identify submicromolar inhibitors. Docking studies supported by in vitro activity measurements suggest that compounds bind to the active site with a salt-bridge characteristic to DAAO inhibitor binding. In addition, displacement of and interaction with the loop covering the active site contributes significantly to the activity of the most potent compounds.

Evaluation of US 2016/0115161 A1: isoindoline compounds and methods of their use

ABSTRACT Introduction: Immunomodulatory drugs (IMIDs®) are small orally available molecules that modulate the immune system and other biological targets through multiple mechanisms of action and have been successfully used in the treatment of myelodysplastic syndrome and multiple myeloma. However, recent studies of their complex mechanism of action revealed their potential in autoimmune diseases and solid tumors, which intensified scientific interest in these compounds. Areas covered: This patent application claims new IMIDs for the treatment of cancer and disorders associated with angiogenesis and inflammation. Substitution of isoindolinone ring on position 5 with urea and amide linkers connected to different aromatic rings lead to very potent inhibitors of TNF-α production with antiproliferative activities against Nemalwa cells and against colorectal, pancreatic, prostate and breast cancer cell lines in sub-nano to low-nanomolar concentration range. Expert opinion: Substitution of position 5 on the isoindolinone ring, which is presented in this invention, is currently the hot spot of Celgene’s research. Results of biological tests, which are superior over those of presently used IMIDs lenalidomide and pomalidomide, make these compounds viable leads for future development of new anticancer drugs against blood and solid cancers.