Boronic Chalcones as Antibacterial Adjuvants: Antibacterial Activity, Synergy With Antibiotics and Siderophore Conjugation.
Almeida Mariana C MC, Lopes Juliana Romano JR, Palmeira Andreia A, Costa Inês I et al.
Antibacterial resistance has reached critical levels and constitutes a global health emergency. Boronic acid derivatives have emerged as promising antibacterial adjuvants, particularly due to their β-lactamase inhibitory potential. Given the growing interest in siderophore-mediated drug delivery as a strategy to enhance antibacterial efficacy, two novel conjugates combining a boronic acid-chalcone derivative with monocatechol siderophore mimetics were synthesized. First, a series of boronic acid-containing chalcones was screened against a panel of bacterial species, including reference strains and clinical isolates. The potential synergistic effects of these compounds in combination with clinically relevant antibiotics, namely oxacillin, vancomycin, and cefotaxime, were also assessed. Five compounds (4-8) exhibited antibacterial activity against Staphylococcus aureus and Enterococcus faecalis (MICs = 16-64 µg/mL) and demonstrated synergistic effects with oxacillin against methicillin-resistant S. aureus (MRSA). Docking studies targeting both the active and allosteric sites of PBP2a were also performed for the most promising compounds, allowing the identification of plausible binding modes at both sites. Two boronic-chalcone conjugates (16-17) with siderophore mimetics were prepared by direct esterification and demonstrated slight improvements in activity against S. aureus. A preliminary cytotoxicity assessment of all compounds indicated a limited selectivity window, highlighting the need for further structural optimization.