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

Abstract

A series of 24 new 1H-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—1H-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 1H-, 13C-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 IC50 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 1H-1,2,3-triazole moiety into the medicinally fascinating boswellic acids skeleton.

3-Acetyl-11-keto-β-boswellic Acid-Based Hybrids Alleviate Acetaminophen-Induced Hepatotoxicity in HepG2 by the Regulation of Inflammatory and Oxidative Stress Pathways: An Integrated Approach

“…47.5, 45.1, 43.8, 40.9, 39.3, 37.6, 34.2, 34.0, 33.2, 30.9, 29.7, 28.9, 27.5, 27.2, 26.6, 24.7, 21.1, 20.5, 19.9, 18.3, 17.5, 13.8; displayed a molecular ion at m/z 614. 9 HepG2 and RAW 264.7 cell lines were obtained from VACSERA, located in Egypt. The growth of the cells was maintained at 37 °C and 5% CO 2 and in DMEM containing 10% fetal bovine serum and 1% pen−strep antibiotics until reaching 80% confluence.…”

“…7 The conjugation of a chalcone scaffold with AKBA also leads to improved cytotoxic activity due to its ability to inhibit pin-1 at (IC 50 = 0.97 μM) to AKBA (IC 50 = 50 μM). 8 In another study, click chemistry was used for the formation of boswellic acid triazole hybrids, which give potent α-glucosidase inhibitory activity (IC 50 = 0.43 μM) in comparison to standard acarbose (IC 50 = 942 μM), 9 as shown in Figure 1A. In this context, oleogum resin from frankincense was reported to possess hepatoprotective properties; 10−12 among its constituents, boswellic acids are extensively studied, especially 3-acetyl-11-keto-β-boswellic acid (AKBA), which emerged as a potent anti-inflammatory agents 13−15 Moreover, AKBA is known to bind to receptors in bile and help in restoration of liver normal architecture.…”

“…( 7 ) The conjugation of a chalcone scaffold with AKBA also leads to improved cytotoxic activity due to its ability to inhibit pin-1 at (IC 50 = 0.97 μM) to AKBA (IC 50 = 50 μM). 8 In another study, click chemistry was used for the formation of boswellic acid triazole hybrids, which give potent α-glucosidase inhibitory activity (IC 50 = 0.43 μM) in comparison to standard acarbose (IC 50 = 942 μM), 9 as shown in Figure 1 A.…”

Meldrum-Based-1H-1,2,3-Triazoles as Antidiabetic Agents: Synthesis, In Vitro α-Glucosidase Inhibition Activity, Molecular Docking Studies, and In Silico Approach

“…Our research group has reported several synthesized bioactive 1 H -1,2,3-triazole analogues with potential biological activities including α-glucosidase inhibitors (Figure ). − …”

Special Issue “Hybrid Drugs: Design and Applications”

“…Their research delved into α-glucosidase inhibition, revealing that all the synthesized derivatives exhibited remarkable potency, exhibiting IC 50 values ranging from 0.22 to 5.32 µM. Notably, these compounds surpassed the efficacy of the standard acarbose by several-fold [12].…”