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

A series of 24 new 1 H -1,2,3-triazole hybrids of 3- O -acetyl-11-keto-β-boswellic acid (β-AKBA ( 1 )) and 11-keto-β-boswellic acid (β-KBA ( 2 )) was designed and synthesized by employing "click" chemistry in a highly efficient manner. The 1,3-dipolar cycloaddition reaction between β-AKBA-propargyl ester intermediate 3 or β-KBA-propargyl ester intermediate 4 with substituted aromatic azides 5a-5k in the presence of copper iodide (CuI) and Hünig's base furnished the desired products-1 H -1,2,3-triazole hybrids of β-AKBA ( 6a-6k ) and β-KBA ( 7a-7k )-in high yields. All new synthesized compounds were characterized by 1 H-, 13 C-NMR spectroscopy, and HR-ESI-MS spectrometry. Furthermore, their α-glucosidase-inhibitory activity was evaluated in vitro. Interestingly, the results obtained from the α-glucosidase-inhibitory assay revealed that all the synthesized derivatives are highly potent inhibitors, with IC 50 values ranging from 0.22 to 5.32 µM. 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 µM, respectively. Molecular docking was carried out to investigate the binding modes of these compounds with α-glucosidase. The molecular docking interactions indicated that that all compounds are well fitted in the active site of α-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 1 H -1,2,3-triazole moiety into the medicinally fascinating boswellic acids skeleton.