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BTEAC Catalyzed Ultrasonic-Assisted Synthesis of Bromobenzofuran-Oxadiazoles: Unravelling Anti-HepG-2 Cancer Therapeutic Potential through In Vitro and In Silico Studies.

ABSTRACT: In this work, BTEAC (benzyl triethylammonium chloride) was employed as a phase transfer catalyst in an improved synthesis (up to 88% yield) of S-alkylated bromobenzofuran-oxadiazole scaffolds BF1-9. These bromobenzofuran-oxadiazole structural hybrids BF1-9 were evaluated in vitro against anti-hepatocellular cancer (HepG2) cell line as well as for their in silico therapeutic potential against six key cancer targets, such as EGFR, PI3K, mTOR, GSK-3β, AKT, and Tubulin polymerization enzymes. Bromobenzofuran structural motifs BF-2, BF-5, and BF-6 displayed the best anti-cancer potential and with the least cell viabilities (12.72 ± 2.23%, 10.41 ± 0.66%, and 13.08 ± 1.08%), respectively, against HepG2 liver cancer cell line, and they also showed excellent molecular docking scores against EGFR, PI3K, mTOR, and Tubulin polymerization enzymes, which are major cancer targets. Bromobenzofuran-oxadiazoles BF-2, BF-5, and BF-6 displayed excellent binding affinities with the active sites of EGFR, PI3K, mTOR, and Tubulin polymerization enzymes in the molecular docking studies as well as in MMGBSA and MM-PBSA studies. The stable bindings of these structural hybrids BF-2, BF-5, and BF-6 with the enzyme targets EGFR and PI3K were further confirmed by molecular dynamic simulations. These investigations revealed that 2,5-dimethoxy-based bromobenzofuran-oxadiazole BF-5 (10.41 ± 0.66% cell viability) exhibited excellent cytotoxic therapeutic efficacy. Moreover, computational studies also suggested that the EGFR, PI3K, mTOR, and Tubulin polymerization enzymes were the probable targets of this BF-5 scaffold. In silico approaches, such as molecular docking, molecular dynamics simulations, and DFT studies, displayed excellent association with the experimental biological data of bromobenzofuran-oxadiazoles BF1-9. Thus, in silico and in vitro results anticipate that the synthesized bromobenzofuran-oxadiazole hybrid BF-5 possesses prominent anti-liver cancer inhibitory effects and can be used as lead for further investigation for anti-HepG2 liver cancer therapy.

SUBMITTER: Irfan A

PROVIDER: S-EPMC9917671 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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BTEAC Catalyzed Ultrasonic-Assisted Synthesis of Bromobenzofuran-Oxadiazoles: Unravelling Anti-HepG-2 Cancer Therapeutic Potential through In Vitro and In Silico Studies.

Irfan Ali A Zahoor Ameer Fawad AF Rasul Azhar A Al-Hussain Sami A SA Faisal Shah S Ahmad Sajjad S Noor Rida R Muhammed Muhammed Tilahun MT Zaki Magdi E A MEA

International journal of molecular sciences 20230203 3

In this work, BTEAC (benzyl triethylammonium chloride) was employed as a phase transfer catalyst in an improved synthesis (up to 88% yield) of S-alkylated bromobenzofuran-oxadiazole scaffolds <b>BF1-9</b>. These bromobenzofuran-oxadiazole structural hybrids <b>BF1-9</b> were evaluated in vitro against anti-hepatocellular cancer (HepG2) cell line as well as for their in silico therapeutic potential against six key cancer targets, such as EGFR, PI3K, mTOR, GSK-3β, AKT, and Tubulin polymerization e ...[more]

PMID: 36769327

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Project description:BackgroundHeterocyclic analogs of curcumin have a wide range of therapeutic potential and the ability to control the activity of a variety of metabolic enzymes.Methods1H-NMR and 13C-NMR spectroscopic techniques were used to determine the structures of synthesized compounds. The agar disc diffusion method and α-amylase inhibition assay were used to examine the antibacterial and anti-diabetic potential of the compounds against α-amylase enzyme inhibitory activity, respectively. DPPH-free radical scavenging and lipid peroxidation inhibition assays were used to assess the in vitro antioxidant potential.Results and discussionIn this work, nine heterocyclic analogs derived from curcumin precursors under ultrasonic irradiation were synthesized in excellent yields (81.4-93.7%) with improved reaction time. Results of antibacterial activities revealed that compounds 8, and 11 displayed mean inhibition zone of 13.00±0.57, and 19.66±00 mm, respectively, compared to amoxicillin (12.87±1.41 mm) at 500 μg/mL against E. coli, while compounds 8, 11 and 16 displayed mean inhibition zone of 17.67±0.57, 14.33±0.57 and 23.33±00 mm, respectively, compared to amoxicillin (13.75±1.83 mm) at 500 μg/mL against P. aeruginosa. Compound 11 displayed a mean inhibition zone of 11.33±0.57 mm compared to amoxicillin (10.75±1.83 mm) at 500 μg/mL against S. aureus. Compound 11 displayed higher binding affinities of -7.5 and -8.3 Kcal/mol with penicillin-binding proteins (PBPs) and β-lactamases producing bacterial strains, compared to amoxicillin (-7.2 and -7.9 Kcal/mol, respectively), these results are in good agreement with the in vitro antibacterial activities. In vitro antidiabetic potential on α-amylase enzyme revealed that compounds 11 (IC50=7.59 µg/mL) and 16 (IC50=4.08 µg/mL) have higher inhibitory activities than acarbose (IC50=8.0 µg/mL). Compound 8 showed promising antioxidant inhibition efficacy of DPPH (IC50 = 2.44 g/mL) compared to ascorbic acid (IC50=1.24 g/mL), while compound 16 revealed 89.9±20.42% inhibition of peroxide generation showing its potential in reducing the development of lipid peroxides. In silico molecular docking analysis, results are in good agreement with in vitro biological activity. In silico ADMET profiles suggested the adequate oral drug-likeness potential of the compounds without adverse effects.ConclusionAccording to our findings, both biological activities and in silico computational studies results demonstrated that compounds 8, 11, and 16 are promising α-amylase inhibitors and antibacterial agents against E. coli, P. aeruginosa, and S. aureus, whereas compound 8 was found to be a promising antioxidant agent.

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Dataset Information

BTEAC Catalyzed Ultrasonic-Assisted Synthesis of Bromobenzofuran-Oxadiazoles: Unravelling Anti-HepG-2 Cancer Therapeutic Potential through In Vitro and In Silico Studies.

Publications

BTEAC Catalyzed Ultrasonic-Assisted Synthesis of Bromobenzofuran-Oxadiazoles: Unravelling Anti-HepG-2 Cancer Therapeutic Potential through In Vitro and In Silico Studies.

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