Synthesis and Structural Characterization of Pyridine-2,6-dicarboxamide and Furan-2,5-dicarboxamide Derivatives.

Derivatives based on pyridine-2-6- and furan-2,5-dicarboxamide scaffolds reveal numerous chemical properties and biological activities. This fact makes them an exciting research topic in supramolecular and coordination chemistry and in discovering new pharmacologically-active compounds. This work aimed to obtain a series of symmetrical pyridine-2-6- and furan-2,5-dicarboxamides through a condensation reaction of the appropriate acyl chlorides and aromatic amides. Successful syntheses were confirmed with NMR spectroscopy. We solved their crystal structures for seven compounds; two pyridine and five furan derivatives. Based on our crystallographic studies, we were able to indicate supramolecular features of the crystals under investigation. Additionally, Hirshfeld surface analysis allowed us to calculate a distribution of intermolecular contacts in the dicarboxamide crystals.

Flexible loops of New Delhi metallo-ß-lactamase modulate its activity towards different substrates.

Two accessory loop regions that are present in numerous variants of New Delhi metallo-ß-lactamases (NDM) are important for the enzymatic activity. The first one is a flexible loop L3 that is located near the active site and is thought to play an important role in the catalytic process. The second region, Ω loop is located close to a structural element that coordinates two essential zinc ions. Both loops are not involved in any specific interactions with a substrate. Herein, we investigated how the length and hydrophobicity of loop L3 influence the enzymatic activity of NDMs, by analyzing mutants of NDM-1 with various deletions/point mutations within the L3 loop. We also investigated NDM variants with sequence variations/artificial deletions within the Ω loop. For all these variants we determined kinetic parameters for the hydrolysis of ampicillin, imipenem, and a chromogenic cephalosporin (CENTA). None of the mutations in the L3 loop completely abolished the enzymatic activity of NDM-1. Our results suggest that various elements of the loop play different roles in the hydrolysis of different substrates and the flexibility of the loop seems necessary to fulfill the requirements imposed by various substrates. Deletions within the Ω loop usually enhanced the enzymatic activity, particularly for the hydrolysis of ampicillin and imipenem. However, the exact role of the Ω loop in the catalytic reaction remains unclear. In our kinetic tests, the NDM enzymes were inhibited in the ß-lactamase reaction by the CENTA substrate. We also present the X-ray crystal structures of the NDM-1, NDM-9 and NDM-12 proteins.