Structure guided SAR exploration resulted in >10,000-fold potency improvement for the BRD4-BD1 bromodomain.
Among them, compounds 6d (242%) and 6f (390%), with nearly 1.6 and 2.6-fold potency compared with 8-MOP (149%) respectively, were recognized as the most promising candidate hits for further pharmacological study of anti-vitiligo.
Compounds 2 (463%) and 18 (438%) with 3 and 4-fold potency compared with 8-MOP respectively, were recognized as the most promising candidate hits for further pharmacological study of anti-vitiligo.
Results indicate that these ring-opened analogs constitute new anti-infective agents with over a 100-fold potency and several fold lower cytotoxicity than cryptolepine from which they are derived.
The most active compound 31, a heptavalent oleanolic acid-β-cyclodextrin conjugate, shows an up to 125-fold potency enhancement by its IC50 value over the corresponding monovalent conjugate and oleanolic acid, disclosing a clear multivalent effect.
To define the inhibitory potency of a selection of resynthesized (glyco peptides systematically, a surface plasmon resonance-based inhibition assay with immobilized asialofetuin was set up. (Glyco Peptides with up to 66-fold potency relative to free lactose as inhibitor were characterized.
Compound 18, with an IC50 of 410 μM, showed 6-fold potency over all other compounds screened.
The linear cyano substituent of 9 enabled a 10-fold potency increase coupled with a significant improvement in the lipophilic binding efficiency (LipE=4.0, Clog D=3.7).
Again, at least a 30-fold potency difference for IgM secretion between PO backbone versions of INH-1 and INH-18 was observed.
The linezolid/sutezolid analogue 19, replacing the morpholine oxygen with a nitrogen, consistently lost approximately 4-fold potency, with the exception of multidrug resistant E. faecium ATCC 51559, where potency was gained.
