Submission Details
Molecule(s):
N#CN(C(=O)[C@@H]1CCS(=O)(=O)c2ccc(Cl)cc21)c1cncc2ccccc12
CN1C[C@@H](C(=O)N(C#N)c2cncc3ccccc23)c2cc(Cl)ccc2S1(=O)=O
N#CN(C(=O)[C@@H]1CCOc2ccc(Cl)cc21)c1cncc2ccccc12
N#CN(C(=O)C1CCS(=O)(=O)c2ccc(Cl)cc21)c1cncc2ccccc12
CN1CC(C(=O)N(C#N)c2cncc3ccccc23)c2cc(Cl)ccc2S1(=O)=O
N#CN(C(=O)C1CCOc2ccc(Cl)cc21)c1cncc2ccccc12
Design Rationale:
The three designs in this submission place a cyano substituent on the amide nitrogen for a cyclic sulfone, a cyclic sulfonamide and chromane. This was originally suggested as a means to form a covalent bond reversibly between ligand and catalytic cysteine and I would not expect it to ‘flip’ the trans/cis conformational preference of the amide in the same way that methylation does. However, the cyano substituent would also address potential ADMET issues (amide hydrolysis in vivo; active efflux linked to amide NH) even if the covalent bond did not form and I’ll link some more detailed discussion in a comment on the submission. I’m assuming that the N-cyano substituent could be put on using cyanogen bromide (I chose an N-methylated cyclic sulfonamide bearing this in mind). I recommend assessing the 3-chlorobenzyl structural prototype PET-UNK-5ecb6237-1 before synthesizing any of these designs. The racemates for the three designs have also been included in the submission.
Other Notes:
Protein-ligand complexes (P1090 A chain) were energy-minimized using Szybki (MMFF94S) fixing the coordinates of the amide nitrogen and oxygen. The PDB file associated with this submission contains the following: [1] P1090 protein structure [2] P1090 A chain crystallographic ligand (MAT-POS-4223bc15-23) [3-5] Non-covalent binding modes predicted predicted for Designs 1-3.