Structural characterization, cytotoxic and enzyme inhibitory profile of a novel triazole-linked ferrocene hybrid of 18?-glycyrrhetinic acid

Abstract

18 beta-Glycyrrhetinic acid (GA) is a pentacyclic triterpene which was obtained from the roots of Glycyrrhiza glabra known for its diverse pharmaceutical applications. The primary aim of this study is to enhance the pharmaceutical properties of GA by modifying it with a 1,2,3-triazole-functionalized ferrocene moiety. The hybrid compound 3 was synthesized by amide functionalization of GA at the C-30 position with ferrocene, linked via a 1,4-disubstituted 1,2,3-triazole bridge. Additionally, the C-3 hydroxyl group of GA was converted into an acetyl ester. The hybrid compound 3 was characterized using FT-IR, NMR (1H and 13C) and HR-MS. The aim of the modification was to enhance the cytotoxic and enzyme inhibitory effects of GA. 1,2,3,-Triazole substituted ferrocene (1), C-3 acetylated GA and the hybrid compound 3 were tested on A549, MCF-7, HCT-116, and PC-3 cancer cell lines. MCF-7 and HCT-116 cells showed the highest sensitivity to the compounds. Compound 3 showed more cytotoxicity than both GA and compound 1 with IC50 values of 23.97 and 50 mu M in MCF-7 and HCT-116 cells, respectively. Morphological analysis indicated that compound 3 induced apoptotic cell death. In addition, the inhibitory effect of compounds on carbonic anhydrase I-II isoenzymes (hCAI-II), acetylcholinesterase/butyrylcholinesterase (AChE/BChE) enzymes, and alpha-glucosidase was tested. According to the results, compound 3, exhibited the strongest inhibitory properties for all enzymes tested with IC50 values of 0.0323, 0.3058, 0.0078, 0.0090 and 0.0120 mu M, respectively. Molecular docking studies were performed to investigate the ligand-target protein interactions. Incorporating an organometallic sandwich-like compound ferrocene into GA via a 1,2,3-triazole bridge appears to be an effective strategy for modifying and enhancing its bioactivity.