Design, Synthesis, and Antimicrobial Evaluation of Novel Chalcone-based Derivatives of Gallic Acid

Introduction: The global rise in antimicrobial resistance highlights the urgent need for new therapeutic agents. This study investigates chalcone-based derivatives of gallic acid as potential antimicrobial compounds. Method: Chalcone derivatives (2a–4c) were synthesized via methylation, Grignard reaction, Claisen-Schmidt condensation, and cyclization. Structural confirmation was achieved using FTIR, NMR, and mass spectrometry. The Docking studies were performed against HSP90α (PDB ID: 1UY6), and ADME properties were predicted using QikProp. Antimicrobial activity was assessed using microbroth dilution and agar well diffusion methods against S. aureus, E. coli, K. pneumoniae, A. baumannii, and C. albicans. Results: Compounds 2d and 3c showed the strongest docking interactions with HSP90α, outperforming ciprofloxacin. MIC results indicated that 2d was most effective, with values as low as 0.39 μg/ml for E. coli and C. albicans. Other compounds, such as 3c and 4c, also showed significant activity (MIC 0.78–6.25 μg/ml). ADME profiling predicted high oral absorption and favorable drug-like properties for the most active compounds. Discussion: Electron-withdrawing groups enhanced antimicrobial activity and binding affinity. Docking data supported the in vitro results, revealing key interactions within the HSP90α active site. result: The Claisen-Schmidt condensation was used to create ten chalcone derivatives of gallic acid. The compounds' structures were verified by spectroscopic data. The antibacterial properties of the compounds were examined. All synthesised compounds have a docking score between -9.472 and -5.411 with HSP90 alpha. (PDB ID - IYU6) In the active pocket of HSP90alpha, compounds 2d and 3c, which shown the most promising in vitro antimicrobial activity, also had the highest docking scores (-9.472 and -9.234, respectively), in comparison to Ciprofloxacin's -7.836. The ADME profile of the most active derivative, 2d and 3c, which was determined by combining in-vitro and docking results, was predicted using the QikProp tool of the Schrodinger software, Maestro version 10.5. After being evaluated, it was found that the projected values for 2d, 3c, and Ciprofloxacin for a number of ADME parameters were either good or within an acceptable range. The results of the antimicrobial test showed considerable antibacterial activity when the minimum inhibitory concentrations (MIC) of chalcone derivatives of Gallic acid (2a-2d) were evaluated against S. aureus, E. coli, K. pneumoniae, A. baumannii, and C. albicans. Compound 2d was the most potent of the compounds examined; its minimum inhibitory concentration (MIC) for S. aureus and K. pneumoniae was 0.78 µg/ml, E. coli was 0.39 µg/ml, A. baumannii was 1.56 µg/ml, and C. albicans was 0.39 µg/ml. This indicates that 2d is more effective than other treatments at preventing the growth of fungi, bacteria, and gram-positive and gram-negative bacteria. With MIC values ranging from 0.78 to 6.25 µg/ml, other derivatives like Compound 4c, 3c, and 3a also showed noteworthy antibacterial activity, suggesting their potential efficacy against a wide range of infections. These findings underscore the potential of certain chalcone derivatives, particularly compound 2d, as potent broad-spectrum antimicrobial agents capable of tackling bacterial and fungal infections, highlighting the need for further in vivo studies and mechanistic evaluations to explore their clinical applications. Conclusion: Chalcone derivatives, particularly 2d, show promise as broad-spectrum antimicrobial agents. Their structural and pharmacokinetic profiles support further development for therapeutic use.