Discovery of Novel Nonsteroidal Anti-Inflammatory Drugs and Carbonic Anhydrase Inhibitors Hybrids (NSAIDs–CAIs) for the Management of Rheumatoid Arthritis

Herein
we report the design as well as the synthesis of a new series
of dual hybrid compounds consisting of the therapeutically used nonsteroidal-anti-inflammatory
drugs (NSAIDs; i.e., indometacin, sulindac, ketoprofen, ibuprofen,
diclofenac, ketorolac, etc., cyclooxygenase inhibitors) and the carbonic
anhydrase inhibitor (CAIs) fragments of the sulfonamide type. Such
compounds are proposed as new tools for the management of ache symptoms
associated with rheumatoid arthritis (RA) and related inflammation
diseases. The majority of the hybrids reported were effective in inhibiting
the ubiquitous human (h) CA I and II as well as the RA overexpressed
hCAs IX and XII isoforms, with KI values
comprised of the low-medium nanomolar ranges. The antihyperalgesic
activity of selected compounds was assessed by means of the paw-pressure
and incapacitance tests using an in vivo RA model, and among them
the hybrids 6B and 8B showed potent antinociceptive
effects lasting up to 60 min after administration.