2-Hydroxy-5-(3,5,7-trihydroxy-4-oxo-4H-chromen-2-yl)phenyl (E)-3-(4-hydroxy-3-methoxyphenyl)acrylate: Synthesis, In Silico Analysis and In Vitro Pharmacological Evaluation

Abstract

Quercetin and ferulic acid are two phytochemicals extensively represented in the plant kingdom and daily consumed in considerable amounts through diets. Due to a common phenolic structure, these two molecules share several pharmacological properties, e.g., antioxidant and free radical scavenging, anti-cancer, anti-inflammatory, anti-arrhythmic, and vasorelaxant. The aim of the present work was the combination of the two molecules in a single chemical entity, conceivably endowed with more efficacious vasorelaxant activity. Preliminary in silico studies herein described suggested that the new hybrid compound bound spontaneously and with high affinity on the KCa1.1 channel. Thus, the synthesis of the 3′-ferulic ester derivative of quercetin was achieved and its structure confirmed by 1H- and 13C-NMR spectra, HSQC and HMBC experiments, mass spectrometry, and elementary analysis. The effect of the new hybrid compound on vascular KCa1.1 and CaV1.2 channels revealed a partial loss of the stimulatory activity that characterizes the parent compound quercetin. Therefore, further studies are necessary to identify a better strategy to improve the vascular properties of this flavonoid.

4-Methoxyphenethyl (E)-3-(o-tolyl)acrylate

“…The 1 H NMR spectrum of the product confirmed the absence of the carboxylic proton signal of the 4-metylcinnamic acid and exhibited clearly the presence of two triplet signals of the two methylene group protons at 2.95 and 4.37 ppm and a singlet signal of the methoxy group protons at 3.79 ppm for the 4-methoxyphenethyl group. It is strongly supported by the 13 C NMR spectrum, which gave signals at 34.42 and 65.36 ppm for the two methylene carbons and a signal at 55.35 ppm for methoxy carbon, and a signal at 167.66 ppm for carbonyl carbon. The IR spectrum showed the presence of carbonyl stretching vibrations at 1707 cm −1 and C-O stretching vibrations at 1163 cm −1 for the ester group.…”

“…1 H NMR (400 MHz, CDCl 3 ) δ 2.42 (s, 3H); 2.95 (t, J = 6.0 Hz, 2H); 3.80 (s, J = 7.6 Hz, 3H); 4.37 (t, J = 6.0 Hz, 2H); 6.33 (d, J = 16.0 Hz, 1H); 6.85 (d, J = 9.2 Hz, 2H); 7.17-7.27 (m, 5H); 7.95 (d, J = 16.0 Hz, 1H); 7.53 (d, J = 7.6 Hz, 1H). 13…”

“…The synthesis of esters can also be carried out using 1,1 -carbonyldiimidazole (CDI) [11] as a coupling agent; however, the resultant intermediate is less reactive than the acyl chloride intermediate [12]. Hydroxybenzotriazole (HOBt) is usually added to the other coupling reagents, such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) [13]; however, concerns have been raised due to its explosive properties [14]. On the other hand, 2-methyl-6-nitrobenzoic anhydride (MNBA) showed great promise in the synthesis of carboxylic esters [15].…”