Evaluation of Anti-herpetic and Antioxidant Activities, and Cytotoxic and Genotoxic Effects of Synthetic Alkyl-Esters of Gallic Acid

Abstract

The n-alkyl esters of gallic acid (CAS 13857-8) have a diverse range of uses as antioxidants in food, cosmetics and pharmaceutical industries. Pharmaceutical studies performed with these compounds have found that they have many therapeutic potentialities including anti-cancer, antiviral and antimicrobial properties. However, more interest has been devoted to their antioxidant activity due to the ability to scavenge and reduce reactive oxygen species (ROS) formation. In this study, gallic acid and 14 different alkyl gallates were tested. The cytotoxicity and anti-herpetic (HSV-1, KOS and 29-R strains) activity were studied by using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) colorimetric assay and the cell viability by using the Trypan blue dye exclusion method. The genotoxicity was studied by the Comet assay and the antioxidant activity by using the DPPH (1,1-diphenyl-2-picrylhydrazyl) radical scavenging and microsomal lipid peroxidation-inhibiting activities. The results showed that all the tested compounds have anti-herpetic activity at non cytotoxic concentrations with selectivity indices (SI = CC50/EC50) varying from 0.89 to 18.34, depending on the used HSV-1 strain. It was observed that all tested alkyl gallates showed some degree of genotoxicity, at the tested concentrations, except cetyl gallate, at 256.60 micromol/L (p <0.05, t-Student test), probably induced by ROS released by infected cells and/or by the alkyl gallates that were not antioxidants, at the tested concentrations, in which they demonstrated anti-herpetic activity. The hydroxyl groups can induce DNA damage due interactions with some metal ions, which are naturally present in the culture medium supplemented with fetal bovine serum, probably explaining the genotoxicity detected. However, the obtained results showed considerable antioxidant activity at smaller concentrations, when compared to quercetin which is considered as a reference drug due to its already described antioxidant potential: DPPH radical scavenging activity with IC50 values varying from 17 to 31 micromol/L; and microsomal lipid peroxidation-inhibiting activity with IC50 values varying from 21 to 59 micromol/L. It was observed that the presence of hydroxyl groups in these molecules is important for their pharmacological profile, but the length of the lateral carbonic chain does not have considerable influence.

Synthetic compounds from an in house library as inhibitors of falcipain-2 from Plasmodium falciparum

“…The 110 assayed synthetic compounds (Table S1, Supplementary information), were prepared as described in our previous reports [19][20][21][22][23][24][25][26][27][28][29] . Reagents were obtained from Sigma-Aldrich Õ (St. Louis, MO) and solvents from Vetec (Duque de Caxias, RJ, Brazil).…”

“…Alternatively, the mixture was dissolved in dioxane (10 mL) and p-toluenesulfonic acid (0.3 mL), and heated for 2-4 h in bath oil under vacuum. All products were purified by column chromatography 19 . The purity of the compounds was confirmed by melting point measurement (with a MGAPF-301 apparatus), infrared spectroscopy (in an Abb Bomen FTLA 2000 spectrometer on KBr disks; Zurich, Switzerland) and 1 H and 13 C nuclear magnetic resonance spectroscopy (on a Varian Oxford AS-400 400 MHz instrument; Agilent Technologies, Santa Clara, CA), as well as elementary analysis (carried out using a CHNS EA 1110).…”

“…The alkyl esters of gallic acid are derived from the natural triphenol flavonoid gallic acid and are widely used in food and pharmaceutical industries as antioxidants 13 . Several reports have documented the properties of natural or synthesized chalcones, benzohydrazides and alkylesters of gallic acid, which include antitumoral, antiinflammatory, antimicrobial and antiviral, among other biological activities [14][15][16][17][18][19] . Chalcones and benzohydrazides had already been studied as antimalarial compounds [14][15][16] and as FP-2 inhibitors 9 .…”

Antimetastatic activity and low systemic toxicity of tetradecyl gallate in a preclinical melanoma mouse model

“…All other reagents were purchased from Sigma Chemical Company (St. Louis, MO, USA). Tetradecyl gallate was synthesized and characterized as described elsewhere [8], and was numbered according to the size of the carbon chain (14 carbons). This compound was dissolved in 100% dimethylsulfoxide (DMSO) (Merck, Darmstadt, GE) and diluted in cell culture medium to a final concentration of 0.1%.…”

“…For instance, methyl gallate is more effective than gallic acid in inhibiting oral bacterial growth and the formation of Streptococcus mutans biofilms [6]. Moreover, synthetic gallic acid derivatives with eight or more carbon atoms in the lateral chain are more efficient than gallic acid in anti-viral, anti-fungal, antioxidant, and anticancer activities [8][9][10][11]. These biological activities have been correlated to the amphipathic character of these ester derivatives.…”