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. 2017 Jul 25;22(8):1247.
doi: 10.3390/molecules22081247.

Multifunctional Cinnamic Acid Derivatives

Aikaterini Peperidou  1 , Eleni Pontiki  2 , Dimitra Hadjipavlou-Litina  3 , Efstathia Voulgari  4 , Konstantinos Avgoustakis  5
Affiliations

Multifunctional Cinnamic Acid Derivatives

Aikaterini Peperidou et al. Molecules. .

Abstract

Our research to discover potential new multitarget agents led to the synthesis of 10 novel derivatives of cinnamic acids and propranolol, atenolol, 1-adamantanol, naphth-1-ol, and (benzylamino) ethan-1-ol. The synthesized molecules were evaluated as trypsin, lipoxygenase and lipid peroxidation inhibitors and for their cytotoxicity. Compound 2b derived from phenoxyphenyl cinnamic acid and propranolol showed the highest lipoxygenase (LOX) inhibition (IC50 = 6 μΜ) and antiproteolytic activity (IC50 = 0.425 μΜ). The conjugate 1a of simple cinnamic acid with propranolol showed the higher antiproteolytic activity (IC50 = 0.315 μΜ) and good LOX inhibitory activity (IC50 = 66 μΜ). Compounds 3a and 3b, derived from methoxylated caffeic acid present a promising combination of in vitro inhibitory and antioxidative activities. The S isomer of 2b also presented an interesting multitarget biological profile in vitro. Molecular docking studies point to the fact that the theoretical results for LOX-inhibitor binding are identical to those from preliminary in vitro study.

Keywords: antiproteolytic activity; cinnamic acids; lipoxygenase inhibitors; multitarget.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Scheme 1
Scheme 1
Synthesis of cinnamic acids. Reagents and reaction conditions: (a) pyridine; CH2(COOH)2; piperidine; reflux; 120–140 °C; 4 h; (b) acetone, 4 M aqueous solution of NaOH; reflux 4 h.
Scheme 2
Scheme 2
Synthesis of cinnamic amides. Reagents and reaction conditions: (i) dry CH2Cl2/Et3N; BOP-reagent; stirring at r.t. for 24 h.
Scheme 3
Scheme 3
Synthesis of cinnamic esters 1c–d. Reagents and reaction conditions: (i) Mono-esterification: Meldrum acid, toluene, 4 h reflux; (ii) Condensation: pyridine, piperidine, stirring at r.t. for 24 h.
Scheme 4
Scheme 4
Synthesis of cinnamic derivatives 1e–f. Reagents and reaction conditions: dry CH2Cl2/Et3N; BOP-reagent; stirring at r.t. for 24 h.
Figure 1
Figure 1
Cytotoxicity of compounds on L929 cells (24 h incubation), as PI% values. The lines on the bars indicate standard deviation. Asterisks indicate statistical significance of difference between the respective compound and atenolol at the respective concentration (* p < 0.05, ** p < 0.01, *** p < 0.001).
Figure 2
Figure 2
Docking pose of 2b (depicted in blue and red) bound to soybean lipoxygenase (LOX-1). The iron ion is depicted as an orange sphere.
Scheme 5
Scheme 5
Synthesis and isolation of (S)-N-(2-hydroxy-3-(naphth-1-yloxy) propyl)-N-isopropyl-3-(3-phenoxy-phenyl) acrylamide (S-2b).
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