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Molecules 2014, 19(12), 20197-20226; doi:10.3390/molecules191220197

Multitarget Molecular Hybrids of Cinnamic Acids

1
Department of Pharmaceutical Chemistry, School of Pharmacy, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece
2
Department of Physiology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece
3
Laboratory of Hygiene and Environmental Protection, Medical School, Democritus University of Thrace, Dragana (Campus), Alexandroupolis 68100, Greece
*
Author to whom correspondence should be addressed.
Received: 27 October 2014 / Revised: 14 November 2014 / Accepted: 25 November 2014 / Published: 2 December 2014
(This article belongs to the Special Issue Cinnamic Acids Hybrids with Biological Interest)
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Abstract

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 (IC50 = 0.34 μΜ and 98.1%, whereas the hybrid 3b of bromobenzyloxycinnamic acid and hymechromone exhibited simultaneously good LOX inhibitory activity (IC50 = 50 μΜ) and the highest anti-proteolytic activity (IC50= 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
Keywords: hybrids; cinnamic acids; multitarget; lipoxygenase inhibitors; antiproteolytic activity; analgesics; anti-inflammatories hybrids; cinnamic acids; multitarget; lipoxygenase inhibitors; antiproteolytic activity; analgesics; anti-inflammatories
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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. (CC BY 4.0).

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MDPI and ACS Style

Peperidou, A.; Kapoukranidou, D.; Kontogiorgis, C.; Hadjipavlou-Litina, D. Multitarget Molecular Hybrids of Cinnamic Acids. Molecules 2014, 19, 20197-20226.

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