Design, Synthesis, and Preliminary Biological Evaluation of Pyrrolo[3,4-c]quinolin-1-one and Oxoisoindoline Derivatives as Aggrecanase Inhibitors

A small set of aggrecanase inhibitors based on the pyrrolo[3,4-c]quinolin-1-one or oxoisoindoline frameworks bearing a 4-(benzyloxy)phenyl substituent and different zinc binding groups were rationally designed and evaluated in silico by docking studies using the crystal structure of the ADAMTS-5 catalytic domain (PDB code: 3B8Z). The designed compounds were synthesized via straightforward routes and tested for their potential inhibitory activity against ADAMTS-5 and ADAMTS-4. Among the compounds containing the pyrrolo[3,4-c]quinolinone tricyclic system, hydroxamate derivative 2b inhibited both ADAMTS-5 and ADAMTS-4, with IC(50) values in the submicromolar range and an inhibitory profile very similar to that of reference carboxylate derivative 11. Conversely, the corresponding carboxylate derivative 2a was significantly less active and unable to discriminate between ADAMTS-5 and -4. The structure-activity relationship analysis of pyrroloquinolinone derivatives 2 a-i suggests that the carboxylate or hydroxamate groups of compounds 2a,b play a key role in the interaction of these compounds with ADAMTS-5 and -4. On the other hand, the oxoisoindoline derivatives 3a,b lack significant ADAMTS-4 inhibitory activity and inhibit ADAMTS-5 showing IC(25) values in the micromolar range.