Submission Details
Molecule(s):
CC(C)(C)c1ccc(N(C(=O)C2(C#N)CC2)C(C(=O)NCCc2cccc(F)c2)c2cccnc2)cc1
CC(C)(C#N)C(=O)N(c1ccc(C(C)(C)C)cc1)C(C(=O)NCCc1cccc(F)c1)c1cccnc1
CC(C)(C)c1ccc(N(C(=O)C(F)(F)C#N)C(C(=O)NCCc2cccc(F)c2)c2cccnc2)cc1
CC(C)(C)c1ccc(N(C(=O)CC#N)C(C(=O)NCCc2cccc(F)c2)c2cccnc2)cc1
Design Rationale:
These designs aim to present a nitrile warhead to the catalytic cysteine and the compounds would accessed by using the appropriate alpha-cyano carboxylic acids in the Ugi synthesis
Other Notes:
The designs are ordered by perceived attractiveness and I would recommend starting with 1st (cyclopropane linker). The nitrile in the 3rd design (CF2 linker) is likely to be the most electrophilic of the nitriles in the set. The 4th design is likely to be the most synthetically accessible of the set and may allow the idea to be tested easily. However, using CH2 to link a nitrile to a carbonyl group can lead to problems (potential for enolisation and carbanion formation) with stability and assay interference. The pdb file contains a (modified) 6w63 crystal structure and the fluorophenethyl in each of the designs has been truncated to methyl in the pdb file. Proposed binding modes were generated by first modelling the des-cyano structures and then editing in the imine groups. No attempt was made to model the covalent bond explicitly.