Background: The rise of multidrug-resistant (MDR) bacteria poses a significant challenge to global public health, contributing to increased morbidity and mortality rates. In this context, the repurposing of existing drugs has emerged as a promising strategy. In this study, hydralazine (HDZ), a vasodilator used as an antihypertensive since 1952, demonstrated antibacterial and antibiofilm activity against both Gram-positive and Gram-negative bacteria. Methods: In this study, the antibacterial activity of the antihypertensive hydralazine (HDZ) was evaluated against Gram-positive and Gram-negative strains through minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), growth curve with MIC and sub-MIC doses, combinatorial effect with gentamicin, scanning electron microscopy (SEM), molecular docking, and antibiofilm activity. Results: The MIC and MBC values ranged from 39.5 to 1.250 μg/mL, respectively. A change in the growth kinetics of the strains was observed when exposed to MIC and 1/2 MIC values, with a delay in the phases of up to 12 h. The combinatorial effect with gentamicin demonstrated an additive and indifferent potential when combined with HDZ. Conclusions: Furthermore, hydralazine showed antibiofilm activity against the tested strains, including MRSA. Electron microscopy analysis revealed significant changes in bacterial morphology when exposed to the MIC dose of HDZ for 4 h. The overall results of the study indicate hydralazine as a potential agent in the fight against bacterial infections.

Introduction: Inflammation is a fundamental physiological response. Currently available drugs, such as nonsteroidal anti-inflammatory drugs (NSAIDs), are effective, yet they present significant limitations, including gastrointestinal and hepatic toxicities alongside compromised safety during long-term administration. In this context, natural compounds with alternative pharmacological profiles have attracted increasing attention. Taxifolin, a flavanonol found in several plant species, has been suggested to possess anti-inflammatory properties. Therefore, the present study aimed to evaluate the in silico anti-inflammatory potential of taxifolin in comparison with therapeutically utilized NSAIDs. Methods: A total of 71 nonsteroidal anti-inflammatory drugs (NSAIDs) retrieved from the IUPHAR/BPS Guide to Pharmacology database were screened and compared with taxifolin through in silico molecular docking analyses targeting human cyclooxygenase isoforms COX-1 (PDB ID: 6Y3C) and COX-2 (PDB ID: 5IKQ). Ligand structures were prepared and optimized prior to docking using AutoDock Vina, with protocol validation performed through redocking analyses against co-crystallized ligands. Binding affinities, ligand-receptor interactions, and conformational stability within the catalytic pockets were evaluated. In addition, pharmacokinetic and toxicological properties were predicted using ADMET-based computational tools, including assessments of absorption, metabolism, cytochrome P450 interactions, clearance, and toxicity-related parameters. Zebrafish, in a carrageenaninduced inflammation model, were used to assess the in vivo toxicity and anti-inflammatory potential of the tested taxifolin. Results: Docking analyses demonstrated that taxifolin exhibits competitive binding affinities toward both cyclooxygenase isoforms, with interaction energies comparable to several clinically used NSAIDs. Favorable interactions were observed within the catalytic sites of both COX-1 and COX-2. ADMET predictions further indicated a favorable pharmacokinetic profile, including favorable gastrointestinal absorption and lower predicted toxicity compared with several synthetic NSAIDs. Taxifolin presented no signs of acute toxicity and demonstrated a significant effect in reducing carrageenan-induced inflammation. Discussion: The distinction between COX-1, a constitutive isoform associated with physiological homeostasis, and COX-2, an inducible isoform linked to pathological inflammation, has guided the development of anti-inflammatory drugs for decades. The ability of taxifolin to interact with the catalytic sites of both isoforms suggests a potential mechanism compatible with cyclooxygenase inhibition while maintaining a favorable predicted safety profile. These findings highlight the relevance of exploring natural flavonoids as molecular scaffolds for the development of new anti-inflammatory strategies. Conclusion: Taken together, this study supports taxifolin as a natural compound of translational interest with potential for the development of novel anti-inflammatory agents or semi-synthetic derivatives. However, further in vitro and in vivo studies are necessary to confirm its pharmacological activity and clinical applicability.