In an attempt to synthesize potential new multitarget agents, 11 novel hybrids incorporating cinnamic acids and paracetamol, 4-/7-hydroxycoumarin, benzocaine,
p-aminophenol and
m-aminophenol were synthesized. Three hybrids—
2e,
2a,
2g—and
3b were found to be multifunctional agents. The hybrid
2e derived from the phenoxyphenyl cinnamic acid and
m-acetamidophenol showed the highest lipoxygenase (LOX) inhibition and analgesic activity (IC
50 = 0.34 μΜ and 98.1%, whereas the hybrid
3b of bromobenzyloxycinnamic acid and hymechromone exhibited simultaneously good LOX inhibitory activity (IC
50 = 50 μΜ) and the highest anti-proteolytic activity (IC
50= 5 μΜ). The hybrid
2a of phenyloxyphenyl acid with paracetamol showed a high analgesic activity (91%) and appears to be a promising agent for treating peripheral nerve injuries. Hybrid
2g which has an ester and an amide bond presents an interesting combination of anti-LOX and anti-proteolytic activity. The esters were found very potent and especially those derived from paracetamol and
m-acetamidophenol. The amides follow. Based on 2D-structure–activity relationships it was observed that both steric and electronic parameters play major roles in the activity of these compounds. Molecular docking studies point to the fact that allosteric interactions might govern the LOX-inhibitor binding.
View Full-Text
►▼
Show Figures
This is an open access article distributed under the
Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited