Bioisosteric Development of Multitarget Nonsteroidal Anti-Inflammatory Drug–Carbonic Anhydrases Inhibitor Hybrids for the Management of Rheumatoid Arthritis

Multitarget nonsteroidal anti-inflammatory drug (NSAID)–carbonic
anhydrase inhibitor (CAI) agents for the management of rheumatoid
arthritis are reported. The evidence of the plasma stability of the
amide-linked hybrids previously reported prompted us to investigate
their pain-relieving mechanism of action. A bioisosteric amide to
ester substitution yielded a series of derivatives showing potent
target CAs inhibition and to undergo cleavage in rat or human plasma
depending on the NSAID portion. A selection of derivatives were assayed in vitro to indirectly evaluate their effect on COX-1 and
COX-2. MD simulations demonstrated that the entire hybrids are also
able to efficiently bind the COX active site. In a rat model of RA,
the most promising derivative (5c) showed major antihyperalgesic
action compared with the equimolar coadministration of the single
agents. The gathered data provided new insights on the action mechanism
of these multitarget compounds, which induce markedly improved pain
relief compared with the parent NSAIDs.