Abstract

Background: Glycyrrhetinic acid (GA) is a biologically active triterpenoid acid, isolated from the root of the Glycyrrhiza plant species. In our earlier studies, the semisynthetic analogs of GA have been reported to possess improved anticancer activities against various cell lines, antimalarial, and antifilarial activities.

Objective: Synthesis of novel C-3 aryl ester derivatives and evaluation of antitubercular activity in order to study structure activity relationship (SAR).

Methods: GA was isolated and characterized from roots of Glycyrrhiza glabra and converted to its various C-3 aryl ester derivatives via the protection of C-30 carboxylic group. Antitubercular activity was determined against Mycobacterium tuberculosis H37Ra by Agar dilution assay. The in silico docking was performed for the most active analogue against three antitubercular targets, catalase peroxidase, dihydrofolate reductase and enoyl-ACP reductase.

Results: The derivatives, Methyl glycyrrhetinate (GA-1), 3-O-(4-methyl-phenyl)-ethanoyl methyl glycyrrhetinate (GA-1a), 3-O-(4-fluoro phenyl)-ethanoyl methyl glycyrrhetinate (GA-1c), 3-O-(4-methoxy trans cinnamyl)-ethanoyl methyl glycyrrhetinate (GA-1e) and 3-O-{(4-chlorophenyl)-ethanoyl methyl glycyrrhetinate (GA-1g) showed improved antitubercular activity (in the range 38.76 to 51.546 mM) over the parent molecule (MIC >106.157 mM). The derivative, 3-O-(4-aminobenzoyl)- methyl glycyrrhetinate (GA-1h) was found most active (MIC 20.695 mM), which was further supported by high binding affinity with the selected antitubercular target proteins in in silico docking studies.

Conclusion: Synthetic modifications on GA led to C-3 aryl ester derivatives with improved antitubercular activities. Further studies for the development of GA-1h as potential antitubercular lead is therefore warranted.

Keywords: Glycyrrhetinic acid, Triterpenoids, Semi-synthesis, Antitubercular, Docking, In Vitro, In Silico.

Graphical Abstract