Ultrasonic-Assisted Synthesis of Heterocyclic Curcumin Analogs as Antidiabetic, Antibacterial, and Antioxidant Agents Combined with in vitro and in silico Studies

Abstract

Background: Heterocyclic analogs of curcumin have a wide range of therapeutic potential and the ability to control the activity of a variety of metabolic enzymes.

Methods: ¹H-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 discussion: In 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.

Conclusion: According 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.

Keywords: ADMET prediction; antibacterial; antioxidant; heterocyclic curcumin analogs; molecular docking; ultrasonic-irradiation; α-amylase.

Scheme 1

Synthesis of monocarbonyl curcumin compounds. Reagent and conditions: (a) NaOH (20%), ethanol, rt, stir for 1 h.

Scheme 2

Synthesis of dehydrozingerone-based monocarbonyl curcumin derivatives. Reagent and conditions: (a) NaOH (20%), rt, stir for 1 h; (b) substituted benzaldehyde, KOH (30%), ethanol, rt, stir for 2–3 h, overnight.

Scheme 3

Ultrasonic irradiation-assisted synthesis of heterocyclic curcumin analogs (8–16). Reagents and conditions: (a) hydrazine hydrate, EtOH; (b) NH₂CONH₂, 40% NaOH, EtOH; (c) Na metal, ethanol; (d) Imidazole, 25 mol% K₃PO₄, CH₃CN,))), 45–60 °C, 250 W for 30–60 min.

Figure 1

Diameter of inhibition zone of the synthesized compounds (8–16) in mm (mean ± SD) at 250 and 500 μg/mL concentrations.

Figure 2

IC₅₀ values of antidiabetic and antioxidant activities of synthesized compounds, 8–16 compared to that of standard drugs, acarbose, and ascorbic acid, respectively.

Figure 3

Percentage inhibition of the synthesized compounds (8–16) and the standard drug at the different concentration range.

Figure 4

Percentage lipid peroxidation inhibitory effect in µg/mL of synthesized compounds (8–16) and ascorbic acid.

Figure 5

3D (right) and 2D (left) representations of the binding interactions of 11 against E. coli DNA Gyrase B (PDB ID: 6F86).

Figure 6

3D (right) and 2D (left) representations of the binding interactions of 16 against PqsA (PDB ID: 5OE3).

Figure 7

3D (right) and 2D (left) representations of the binding interactions of 12 against S. aureus Pyruvate Kinase (PDB ID: 3T07).

Figure 8

3D (right) and 2D (left) representations of the binding interactions of 11 against LuxS of S. pyogenes (PDB ID: 4XCH).

Figure 9

3D (right) and 2D (left) representations of the binding interactions of 11 against Penicillin binding proteins (PBPs) (PDB ID: 1VQQ).

Figure 10

3D (right) and 2D (left) representations of the binding interactions of 11 against β-lactamases (PDB ID: 1IYS).

Figure 11

3D (right) and 2D (left) representations of the binding interactions of 8 against Human peroxiredoxin 5 (PDB ID: 1hd2).

Figure 12

3D (right) and 2D (left) representations of the binding interactions of 8 against α-amylase enzyme (PDB ID: 4w93).

Figure 13

3D (right) and 2D (left) representations of the binding interactions of 16 against α-amylase enzyme (PDB ID: 4w93).