Synthesis, antibacterial, antioxidant, molecular docking and ADMET properties of halogenated vanillin azo‑chalcone

Mohamad Azmeer, Hissam and Zainab, Ngaini and Stephenie Ivy, Patrick Mesebasio and Dinie Adilah, Jefree Shahren (2025) Synthesis, antibacterial, antioxidant, molecular docking and ADMET properties of halogenated vanillin azo‑chalcone. Discover Applied Sciences, 7 (654). pp. 1-15. ISSN 3004-9261

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Abstract

The emergence of multidrug-resistant superbugs poses a signifcant global health threat, emphasising the urgent need for innovative antimicrobial agents. Simultaneously, oxidative stress-induced cellular damage highlights the growing demand for efective antioxidants to mitigate harmful efects. Many bactericidal antibiotics exert their efects by inducing oxidative stress, which can contribute to bacterial resistance through enhanced antioxidant defences. This study addresses these interconnected challenges by utilizing natural products such as vanillin as cost-efective and versatile precursors. Herein, a series of vanillin azo precursors (1a–h) were synthesised via a diazo coupling reaction and subsequently modifed through Claisen-Schmidt condensation, yielding chalcone-bearing derivatives (2a–h) with 52–79%. These derivatives (2a–h) (8.13—10.30 mm) exhibited enhanced antibacterial activity against both E. coli and S. aureus compared to 1a–h (7.13—8.10 mm) via the Kirby-Bauer disc difusion method. Additionally, compound 2a–h demonstrated improved antioxidant properties via DPPH assay with IC50 values spanning 13.00 to 175.00 µg/mL, particularly upon incorporating the chalcone moiety compared to 1a–h (>200.00 µg/mL). Among all synthesised compounds, 2d exhibited excellent antibacterial (9.97—10.07 mm) and antioxidant (IC50: 12.57±0.12 µg/mL, IC25: 4.17±0.24 µg/ mL) properties, comparable to standard ampicillin (10.23–12.23 mm) and ascorbic acid (IC50: 13.50±0.08 µg/mL, IC25: 5.17±0.24 µg/mL), respectively. Docking studies were performed using Autodock Tools and AutoDock Vina for compound 2d, revealing a binding afinity of −6.50 kcal/mol comparable with standard norfoxacin (−6.60 kcal/mol). These findings highlight vanillin’s promising potential as an antibacterial and antioxidant agent, supported by good ADMET properties. This study provides a valuable contribution to the ongoing search for effective strategies to combat antibiotic resistance and mitigate oxidative stress-related challenges.

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