# Microwave-Assisted Synthesis of Imidazole-Based Chalcones: Modulating Antimicrobial Activity Through Alkoxy Substitutions

## TL;DR

This study synthesizes imidazole-based chalcones with alkoxy substitutions to enhance antimicrobial activity, identifying promising candidates against resistant microbes.

## Contribution

The paper introduces a sustainable synthesis method and demonstrates how alkoxy substitutions modulate antimicrobial efficacy and binding to biofilm regulators.

## Key findings

- Dialkoxy and trialkoxy derivatives showed enhanced antimicrobial activity compared to monoalkoxy compounds.
- IBC20 and IBC23 exhibited strong binding to the biofilm regulator TcaR, suggesting potential allosteric inhibition.
- ADME predictions indicated good drug-likeness and oral absorption for the most active compounds.

## Abstract

Background/Objectives: The emergence of antimicrobial resistance necessitates the development of new and effective antimicrobial agents. In this study, three different series of imidazole-based chalcones (IBC1-25) were designed and synthesised using a sustainable approach, with the aim of identifying compounds with enhanced antimicrobial activity. Methods: A series of monoalkoxy, dialkoxy, and trialkoxy imidazole-based chalcones (IBC1–25) were synthesised and evaluated for their antimicrobial and antifungal activities against a range of microbial strains. Structure-activity relationships were analysed, and molecular docking studies were performed to investigate potential binding interactions with biofilm-associated regulatory proteins. In addition, ADME properties were predicted to assess drug-likeness. Results: Among the monoalkoxy derivatives (IBC1-14), IBC5 exhibited the broadest spectrum of activity, particularly against S. epidermidis. Several dialkoxy analogues (IBC17-21) demonstrated improved potency, with IBC20 showing notably high activity. While IBC22 and IBC25 were largely ineffective, IBC23 and IBC24 displayed significant antibacterial and antifungal activities. Overall, dialkoxy and trialkoxy derivatives exhibited enhanced efficacy, whereas monoalkoxy compounds with bulky or long-chain substituents were generally less active. The presence of multiple alkoxy substituents, such as methoxy and ethoxy groups, on the phenyl ring significantly improved activity, particularly against fungi and Gram-positive bacteria. Molecular docking studies revealed that IBC20 and IBC23 showed favourable binding to the biofilm-associated regulator TcaR, suggesting a potential allosteric inhibition mechanism, while weak interactions were observed with TagF. ADME predictions indicated good oral absorption and compliance with key drug-likeness criteria. Conclusions: The results demonstrate that both the number and type of alkoxy substituents play a critical role in antimicrobial activity. In particular, IBC20 and IBC23 emerge as promising candidates for further development as antimicrobial agents targeting biofilm-associated pathways.