Synthesis, characterization and the biological potential of 4-aminoquinoline derivatives and non-steroidal anti-inflammatory drugs hybrids
aminoquinoline; non-steroidal anti-inflammatory drugs; hybrid molecules; inflammation.
In chronic inflammatory diseases, such as rheumatoid arthritis, the inflammatory process induced by a noxious stimulus cannot be repaired. The usual treatment consists in non-steroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids, as well as disease-modifying antirheumatic drugs (DMARDs), such as chloroquine – a 4-aminoquinoline derivative. In order to achieve a better treatment efficacy, chloroquine and NSAIDs are usually associated. Molecular hybridization is a ligand-based drug design (LBDD) approach that may result in compounds with different pharmacophoric groups and synergistic action. Thus, the aim of this study was to synthetize hybrid molecules of 4-aminoquinoline derivatives with ibuprofen, naproxen, and ketoprofen (NSAIDs), which may present an anti-inflammatory potential, followed by their structural characterization and biological evaluation. The hybrids synthetized are new compounds, which presented an easy route of synthesis through a one-pot methodology: ICEQ, NCEQ, KCEQ, IDAPQ, NDAPQ, KDAPQ. They were well characterized by 1H and 13C NMR, FTIR, and mass spectroscopy, which validated the planned structures. The first one, ICEQ, was chose to evaluate a preliminary anti-inflammatory profile. In the biological evaluation, the MTT assay showed that ICEQ presents significant cytotoxic effects only in concentrations ≥ 10 µM. Then, the secretion of pro-inflammatory cytokine IL-1β was evaluated in macrophages along with the treatment of ICEQ. The hybrid was able to statistically reduce the pro-inflammatory cytokine without interfering in the cell viability in all tested concentrations (0.3, 1.0, and 3.0 µM). Based on that, it can be inferred that this hybrid presents an anti-inflammatory profile, although further studies are necessary to evaluate the real anti-inflammatory potential of all synthesized hybrids.