Submission Details
Molecule(s):
CC(=O)Nc1cncc2c1CCNC2
Cc1ccncc1N1C(=O)CCNC1=O
Cc1ccncc1N1C(=O)CCN(CC(=N)N)C1=O
Cc1ccncc1N1C(=O)CCN(CC(N)=O)C1=O
Cc1ccncc1N1C(=O)CCN(CCC(=N)N)C1=O
Cc1ccncc1N1C(=O)CCN(CCC(N)=O)C1=O
Cc1ccncc1-n1c2c(ccc1=O)N(CC(=N)N)CCC2
Cc1ccncc1-n1c2c(ccc1=O)N(CC(N)=O)CCC2
Cc1ccncc1-n1c2c(ccc1=O)N(CCC(=N)N)CCC2
Cc1ccncc1-n1c2c(ccc1=O)N(CCC(N)=O)CCC2
NC(=O)CCN1CCC(=O)N(c2cncc3c2CCNC3)C1=O
Design Rationale:
The designs are all based on fragment X0107 as the core fragment. Analogues have all been docked using Glide SP to support the various changes. Growing by fusing the fragment with a basic nitrogen-containing piperidine ring might allow for interaction with the proximal Glu166. Linking with fragment X0991 has been attempted with the other analogues, exploring various linker lengths, cyclizations and replacement of the amidine with an amide. The last analogue combines the combination of growing and linking that gives the most potent analogue based on docking score (but the other combinations should probably also be tested).
Other Notes:
Synthesis of these analogues should all be possible using SNAr and N-alkylation reactions.