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In silico studies of bacterial efflux pump inhibition by thioxanthones and their synergistic antibacterial activity
Fernando Durães 1, 2 , Filipa Barbosa 1 , Joana Freitas-Silva 2, 3 , Paulo Costa 2, 3 , Madalena Pinto 1, 2 , Emília Sousa * 1, 2
1  Laboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Portugal
2  Centro Interdisciplinar de Investigação Marinha e Ambiental (CIIMAR), Universidade do Porto, Portugal
3  ICBAS – Institute of Biomedical Sciences Abel Salazar, University of Porto, Portugal

Published: 30 October 2019 by MDPI AG in 5th International Electronic Conference on Medicinal Chemistry session ECMC-5
10.3390/ECMC2019-06300
Abstract:

Efflux pumps are transmembrane transport proteins, ubiquitous in bacteria, that can actively extrude several antimicrobial drugs from within cells into the external environment, allowing bacteria to develop multidrug resistance. Efforts have been put towards a selective, efficient efflux pump inhibitor (EPI), and although some progress has been achieved, no EPIs have been approved in the therapeutic scenario [1]. This problem leads to the inefficacy of a large amount of antimicrobial drugs, with antimicrobial resistance posing one of the most urgent threats concerning health problems of our days.

Thioxanthones are heterocyclic, privileged structures with a dibenzo-γ-thiopyrone scaffold [2]. Previous work by our group has demonstrated the potential of these compounds as human efflux pump modulators [3].

In this scope, a virtual library of approximately 1000 thioxanthones was designed, and in silico studies were performed. The compounds that displayed good docking scores for bacterial efflux pumps and lower scores for P-glycoprotein were selected to be obtained by synthesis.

The synthesis of thioxanthones was performed using a copper-catalysed Ullmann coupling. With this strategy we expect to obtain a library of novel thioxanthones with potential to inhibit efflux pumps and revert multidrug resistance. The structures of the synthetized compounds were determined by 1H and 13C NMR and X-ray crystallography.

Antibacterial activity and synergism assays with antibacterial drugs were performed, with two compounds displaying promising results in combination with antibacterial drugs, although with no relevant antimicrobial activity. Future studies will involve insights into the mechanism of synergy of promising compounds.

Acknowledgements: This work was developed under the Strategic Funding UID/Multi/04423/2019 and Project No. 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.

REFERENCES

[1] Durães, F.; Pinto, M.; Sousa, E., Curr Med Chem 2018, 25, 6030.6069.

[2] Palmeira, A.; Vasconcelos, M. H.; Paiva, A.; Fernandes, M. X.; Pinto, M.; Sousa, E. Biochem Pharmacol 2012, 83 (1), 57-68.

[3] Palmeira, A.; Rodrigues, F.; Sousa, E.; Pinto, M.; Vasconcelos, M. H.; Fernandes, M. X. Chem Biol Drug Des 2011, 78 (1), 57-72.

Keywords: efflux pumps; thioxanthones; antibacterial; synergy
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