Discovery of New Boswellic Acid Hybrid 1H-1,2,3-Triazoles for Diabetic Management: In Vitro and In Silico Studies

A series of 24 new 1H-1,2,3-triazole hybrids of 3-O-acetyl-11-keto-beta-boswellic acid (beta-AKBA (1)) and 11-keto-beta-boswellic acid (beta-KBA (2)) was designed and synthesized by employing click chemistry in a highly efficient manner. The 1,3-dipolar cycloaddition reaction between beta-AKBA-propargyl ester intermediate 3 or beta-KBA-propargyl ester intermediate 4 with substituted aromatic azides 5a-5k in the presence of copper iodide (CuI) and Hunig's base furnished the desired products-1H-1,2,3-triazole hybrids of beta-AKBA (6a-6k) and beta-KBA (7a-7k)-in high yields. All new synthesized compounds were characterized by H-1-, C-13-NMR spectroscopy, and HR-ESI-MS spectrometry. Furthermore, their alpha-glucosidase-inhibitory activity was evaluated in vitro. Interestingly, the results obtained from the alpha-glucosidase-inhibitory assay revealed that all the synthesized derivatives are highly potent inhibitors, with IC50 values ranging from 0.22 to 5.32 mu M. Among all the compounds, 6f, 7h, 6j, 6h, 6g, 6c, 6k, 7g, and 7k exhibited exceptional inhibitory potency and were found to be several times more potent than the parent compounds 1 and 2, as well as standard acarbose. Kinetic studies of compounds 6g and 7h exhibited competitive and mixed types of inhibition, with ki values of 0.84 +/- 0.007 and 1.18 +/- 0.0012 mu M, respectively. Molecular docking was carried out to investigate the binding modes of these compounds with alpha-glucosidase. The molecular docking interactions indicated that that all compounds are well fitted in the active site of alpha-glucosidase, where His280, Gln279, Asp215, His351, Arg442, and Arg315 mainly stabilize the binding of these compounds. The current study demonstrates the usefulness of incorporating a 1H-1,2,3-triazole moiety into the medicinally fascinating boswellic acids skeleton.

Automated summary

A series of 24 new 1H-1,2,3-triazole hybrids of 3-O-acetyl-11-keto-beta-boswellic acid and 11-keto-beta-boswellic acid were synthesized using click chemistry. These compounds exhibited potent α-glucosidase inhibitory activity and showed interactions with amino acids in the active site.