Gallic Acid Alkyl Esters: Trypanocidal and Leishmanicidal Activity, and Target Identification via Modeling Studies

Eight gallic acid alkyl esters (1-8) were synthesized via Fischer esterification and evaluated for their trypanocidal and leishmanicidal activity using bloodstream forms of Trypanosoma brucei and promastigotes of Leishmania major. The general cytotoxicity of the esters was evaluated with human HL-60 cells. The compounds displayed moderate to good trypanocidal but zero to low leishmanicidal activity. Gallic acid esters with alkyl chains of three or four carbon atoms in linear arrangement (propyl (4), butyl (5), and isopentyl (6)) were found to be the most trypanocidal compounds with 50% growth inhibition values of similar to 3 mu M. On the other hand, HL-60 cells were less susceptible to the compounds, thus, resulting in moderate selectivity indices (ratio of cytotoxic to trypanocidal activity) of >20 for the esters 4-6. Modeling studies combining molecular docking and molecular dynamics simulations suggest that the trypanocidal mechanism of action of gallic acid alkyl esters could be related to the inhibition of the T. brucei alternative oxidase. This suggestion is supported by the observation that trypanosomes became immobile within minutes when incubated with the esters in the presence of glycerol as the sole substrate. These results indicate that gallic acid alkyl esters are interesting compounds to be considered for further antitrypanosomal drug development.

Automated summary

Eight gallic acid alkyl esters were synthesized and evaluated for their trypanocidal and leishmanicidal activity. The compounds showed moderate to good trypanocidal activity and low leishmanicidal activity. Among them, the esters with propyl and isopentyl alkyl chains exhibited the most potent trypanocidal activity with a 50% growth inhibition value of about 3 μM. These esters also had low toxicity to human cells, making them potential candidates for antitrypanosomal drug development.