Antimicrobial resistance is a huge public health threat, resulting in an increase of morbidity and mortality rates, high medical costs, among others. Several mechanisms are underlying bacterial resistance, such as the overexpression of drug efflux pumps, permeability changes in the bacterial cell wall or the biofilm formation. Therefore, the search for new antimicrobial agents is an urgent demand.

Chalcones are open-chain flavonoids well-known for their antimicrobial activities, as well as for their ability to revert antibiotic resistance through several mechanisms, including efflux pump inhibitory activity and the inhibition of biofilm formation. Moreover, hybridization of chalcones with 1,2,3-triazole has provided compounds with interesting antimicrobial activities. Considering this, a series of chalcone-1,2,3-triazole hybrids was synthesized and screened for its antibacterial, antifungal, and potential to establish synergy with antibiotics in resistant bacteria. Furthermore, these compounds were evaluated for their ability to act in different bacterial resistance mechanisms, namely the inhibition of bacterial efflux pumps, biofilm formation and quorum-sensing. Firstly, chalcone intermediates were synthesized by Claisen-Schmidt condensation. Then, the triazole ring was incorporated on the chalcone scaffold through the copper catalysed alkyne-azide cycloaddition, giving rise to eight hybrids. Some compounds showed synergic effect in association with antibiotics in resistant strains of Escherichia coli and Enterococcus faecalis, as well as ability to inhibit efflux pumps of Salmonella enterica serovar Typhimurium SL1344 and to inhibit the biofilm formation of Staphylococcus aureus 272123, a methicillin- and oxacillin-resistant clinical isolate. Overall results suggest the potential of these compounds as adjuvants in bacterial resistance modulation.

Acknowledgements: This research was supported by national funds through FCT - Foundation for Science and Technology within the scope of UIDB/04423/2020 and UIDP/04423/2020 (Group of Natural Products and Medicinal Chemistry, CIIMAR) and under the project PTDC/SAU-PUB/28736/2017 (reference POCI-01-0145-FEDER-028736), co-financed by COMPETE 2020, Portugal 2020 and the European Union through the ERDF, and by FCT through national funds, and by the structured program of R&D&I ATLANTIDA (reference NORTE-01-0145-FEDER-000040), supported by the North Portugal Regional Operational Programme (NORTE2020), through the ERDF. This research was also supported by IINFACTS, grant number CHIRALBIOACTIVE‐PI‐3RL‐IINFACTS‐2019 and CHIRALSINTESE_APSFCT_IINFACTS_2021. Daniela Pereira and Fernando Durães acknowledges FCT for their PhD grants (SFRH/BD/147207/2019 and SFRH/BD/144681/2019, respectively).