Bioorg Med Chem. 2018 Jul 15;26(11):2928-2936. doi: 10.1016/j.bmc.2018.02.043. Epub 2018 Feb 23.
Structure activity relationship studies on rhodanines and derived enethiol inhibitors of metallo-β-lactamases.
Zhang D1, Markoulides MS1, Stepanovs D1, Rydzik AM1, El-Hussein A2, Bon C1, Kamps JJAG1, Umland KD1, Collins PM3, Cahill ST1, Wang DY1, von Delft F4, Brem J1, McDonough MA1, Schofield CJ5.
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford OX1 3TA, United Kingdom.
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford OX1 3TA, United Kingdom; The National Institute of Laser Enhanced Science, Cairo University, Egypt.
Diamond Light Source, Harwell Science and Innovation Campus, Didcot OX11 0DE, United Kingdom.
Diamond Light Source, Harwell Science and Innovation Campus, Didcot OX11 0DE, United Kingdom; Structural Genomics Consortium (SGC), University of Oxford, Oxford, OX3 7DQ, UK; (e)Department of Biochemistry, University of Johannesburg, Auckland Park, 2006, South Africa.
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford OX1 3TA, United Kingdom. Electronic address: christopher.schofield@chem.ox.ac.uk.
Bioorg Med Chem. 2018 Jul 15;26(11):2928-2936.
Outlined mechanism for B1 MBL catalysed β-lactam hydrolysis as exemplified by hydrolysis of a carbapenem. The anionic intermediate, but not the tetrahedral intermediate‡, has been observed spectroscopically.
Synthesis of enethiol based β-lactamase inhibitors. (a) Route for preparation of ML302 5a-q analogues and ML302F 6a-q analogues. (b) R groups for 5a-q and 6a-q. MW: microwave irradiation.
Synthesis of the 2,4-dione derivative 10 of ML302.
Synthesis of racemic α-mercaptocarboxylic acids 13a and 13b.
Synthesis of α-hydroxycinnamic acid 17.
Synthesis of α-hydroxy phosphonic acid 22 and α-sulfanyl phosphonic acid 26, , , , , , , , , .
Prior crystallographic analysis revealed that ML302 undergoes fragmentation to form the enethiol inhibitor ML302F (PDB ID: 4PVO), which coordinates to the di-Zn(II) containing active site. All figures are labelled using the BBL numbering scheme.
Superimposition of structures of BcII (turquoise) (PDB ID: 5JMX, 6EUM, 6EWE, 6F2N) with VIM-2 (pink) (PDB ID: 6EW3) showing the similarity in binding modes for 6c (yellow), 6k (salmon), 6L (purple), 6s (green), and ML302F (wheat). In each MBL the thiolate interacts with both Zn(II) ions and the inhibitor carboxylate interacts with Zn2 and (Lys-224 of BcII/Arg233 of VIM-2).
View from a crystal structure of BcII (turquoise) in complex with 6s (green). Active site residues shown as ball-and-stick with atoms coloured C (white), O (red), N (blue), Zn (grey spheres), water (red spheres). Ligand interactions are indicated with black dashed lines. Ligand mFo-DFc OMIT maps contoured to 3.0 σ are shown as light grey mesh.