Antimicrobial and Antibiofilm Activities of Some Antioxidant 3,4-Dihydroxyphenyl-Thiazole-Coumarin Hybrid Compounds: In Silico and In Vitro Evaluation.

Background/Objectives: In this study, we aimed to investigate the antimicrobial and antibiofilm activity of seven hydroxyphenyl-thiazolyl-coumarin hybrid compounds with antioxidant properties (1a-g), previously reported by our group. Methods: The compounds were evaluated in vitro through MIC, MBC, and MFC determinations, and percentage of biofilm (BF) inhibition and in silico, respectively, through molecular docking, molecular dynamics simulations, and ADMETox prediction. Results: All compounds showed antibacterial and antifungal activities. In terms of antibacterial activity, all the compounds were active on Pseudomonas aeruginosa (MICs = 15.62-31.25 μg/mL), Enterococcus faecalis (MICs = 15.62-31.25 μg/mL), and Staphylococcus aureus (MICs = 62.5-125 μg/mL). Regarding the antifungal activity, the effect against Candida albicans was similar to fluconazole (MIC = 15.62 μg/mL), compounds 1b and 1g being the most active against Aspergillus brasiliensis (MIC = 15.62 μg/mL). Furthermore, all compounds were both bactericidal and fungicidal. Regarding the antibiofilm activity, compounds 1d-g showed superior P. aeruginosa BF inhibition compared to gentamicin. The in vitro results for the antibacterial activity were well correlated with the observations drawn in the molecular docking studies, where the best binding affinities (BAs) were observed against P. aeruginosa PAO1 GyrB subunit, and the molecular dynamics simulations confirmed the antibacterial mechanism of compounds 1a, 1b, 1d, 1f, and 1g through GyrB subunit inhibition. Regarding the antifungal activity, all compounds showed better BAs than fluconazole against CYP51 in all instances. ADMETox predictions concluded that all the compounds could have low gastrointestinal absorption and reduced risk of pharmacokinetic interactions. Conclusions: The investigated compounds bring novelty into the actual research due to their dual antibacterial and antibiofilm activity against biofilm-associated P. aeruginosa infections.