Synthesis and biological activity of hydroxycinnamoyl containing antiviral drugs

Abstract

Seven N-hydroxycinnamoyl amides were synthesized by EDC/HOBt coupling of the corresponding substituted cinnamic acids (p-coumaric-, ferulic-, sinapic- and caffeic acids) with influenza antivirals (amantadine, rimantadine and oseltamivir). DPPH (1,1-diphenyl-2-picrylhydrazyl) scavenging abilities and the inhibitory effect on mushroom tyrosinase activity (using L-tyrosine as the substrate) were investigated in vitro. Amongst the synthesized compounds, N-[(E)-3-(3?,4?-dihydroxyphenyl)-2-propenoyl]oseltamivir (1) and N-[(E)-3-(3?,4?-dihydroxyphenyl)-2-propenoyl]rimantadine (4), containing catechol moiety, exhibited the most potent DPPH radical-scavenging activity. Amide (1) displayed also tyrosinase inhibitory effect toward L-tyrosine as the substrate (~50%). Due to its biological activities revealed so far compound (1) can be considered as a promising candidate for a cosmetic ingredient. The synthesized compounds were also investigated for their in vitro inhibitory activity against the replication of influenza virus A (H3N2).

Hybridization of Aminoadamantanes with Cinnamic Acid Analogues and Elucidation of Their Antioxidant Profile

“…In all cases (except with the α-methylcinnamoylamides (4a 2 , 4b 3 , and 4c 1 )), the confguration of the double bond was determined to be E-, based on the high value of the 1 H vicinal coupling constant (3J∼16 Hz). Moreover, the similar trans-confguration was also found in other cinnamic acid amides of aminoadamantanes, previously obtained by us [9,31].…”

“…Moreover, the greatest value of DPPH inhibition percentages was found for cafeoyl derivatives 4a 6 (55.06%) and 4c 6 (51.38%) at the highest concentration of 500 µM. Interestingly, comparing the results obtained for N-cafeoyl-rimantadine (4c 6 ) and cafeic acid by another DPPH methodology [40], previously applied by us [9], a diference in activities was found. Tus, the compounds 4c 6 and CafA at 48 μM in ethanolic media displayed higher %RSA values of 72.58 ± 8.26 and 92.65 ± 2.90, respectively [9], compared to the current methanolic conditions (Figure 1).…”

“…Interestingly, comparing the results obtained for N-cafeoyl-rimantadine (4c 6 ) and cafeic acid by another DPPH methodology [40], previously applied by us [9], a diference in activities was found. Tus, the compounds 4c 6 and CafA at 48 μM in ethanolic media displayed higher %RSA values of 72.58 ± 8.26 and 92.65 ± 2.90, respectively [9], compared to the current methanolic conditions (Figure 1). Indeed, not only the solvent afects the scavenging activity; however, various documented DPPH protocols difer in more than one experimental condition, and the information provided are often contradictory [40].…”

“…Phenylpropenoic acids as substituted cinnamic acids (e.g., ferulic, sinapic, and cafeic acids) and their derivatives (cinnamates and cinnamamides), especially those with phenolic hydroxyl groups, are one of the most important classes of exogenous phenolic antioxidants [6][7][8][9]. Due to the low toxicity and high bioactivity, hydroxycinnamoyl rest is a privileged scafold not only in various natural products (such as food additives) but also in modern drug discovery, as drug-like molecules with potential pharmacological activity [10,11].…”