Submission Details
Molecule(s):
C#CC(=O)c1cccc2cncc(NC(=O)Cc3cccc(Cl)c3)c12
N#C/C=C/C(=O)c1cccc2cncc(NC(=O)Cc3cccc(Cl)c3)c12
O=C(Cc1cccc(Cl)c1)Nc1cncc2cccc(CC(F)(F)F)c12
C#CC(=O)N1CCOc2cncc(NC(=O)Cc3cccc(Cl)c3)c21
C#CC(=O)c1cccc2cncc(N(C)C(=O)Cc3cccc(Cl)c3)c12
N#CCC(C(=O)Nc1cncc2ccccc12)c1cccc(Cl)c1
CN(C(=O)C(CC#N)c1cccc(Cl)c1)c1cncc2ccccc12
N#Cc1ncc2ccccc2c1NC(=O)Cc1cccc(Cl)c1
CN(C(=O)Cc1cccc(Cl)c1)c1c(C#N)ncc2ccccc12
CN(C(=O)Cc1cccc(Cl)c1)c1c(CC(F)(F)F)ncc2ccccc12
O=C(Cc1cccc(Cl)c1)Nc1c(CC(F)(F)F)ncc2ccccc12
C#CC(=O)N1CCOc2cncc(N(C)C(=O)Cc3cccc(Cl)c3)c21
CN(C(=O)Cc1cccc(Cl)c1)c1cncc2cccc(CC(F)(F)F)c12
Design Rationale:
"Double amides" might be synthetically-difficult and might be unstable, react with water or polymerise...My feeling is that they could eject m-chlorophenylacetic acid after addition of the warhead on the NH? Just using DAR-DIA-56cf811e as an exemplar, could we redesign, with the warhead coming off somewhere else? This will need, obviously modelling input from the likes of @PWKenny as I'm probably not pointing towards the Cys any more. By eye, the NH and C=O might form an intramolecular H-bond so, N-methylation might disrupt this. I've also added my vanity CH2CF3 (non covalent but pretty decent, all the same), CF3-ethyl, to interact with a SH and possible nearby protein backbone C=O...
Other Notes:
Using @Daren_Fearon range of warheads on the likes of NAU-LAT-4ce8bf23; DAN-LON-a5fc619e-3 might be further inspiration where this issue would not be anticipated.