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Chiral derivatives of xanthones: synthesis, enantiomeric purity and enantioselectivity in the reversal antimicrobial resistance mechanisms
1, 2 , 3, 4 , 2, 5 , 6 , 2, 5 , 2, 7 , 1, 2, 8 , 6 , * 1, 2 , 3, 4 , * 3, 4
1  Laboratory of Organic and Pharmaceutical Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
2  CIIMAR – Interdisciplinary Centre of Marine and Environmental Research, University of Porto, 4450-208 Matosinhos, Portugal
3  Laboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua Jorge Viterbo Ferreira nº 228, 4050-313 Porto, Portugal
4  Centro Interdisciplinar de Investigação Marinha e Ambiental (CIIMAR), Universidade do Porto, Edifício do Terminal de Cruzeiros do Porto de Leixões, Av. General Norton de Matos s/n, 4050-208 Matosinhos, Portugal
5  ICBAS – Institute of Biomedical Sciences Abel Salazar, University of Porto, 4050-313 Porto, Portugal
6  Department of Medical Microbiology, Albert Szent-Györgyi Health Center and Albert Szent-Györgyi Medical School, University of Szeged, 6725 Szeged, Hungary
7  Laboratory of Microbiology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
8  CESPU, Institute of Research and Advanced Training in Health Sciences and Technologies (IINFACTS), 4585-116 Gandra, Portugal
Academic Editor: Alfredo Berzal-Herranz (registering DOI)

The design of peptidomimetic small molecules, such as amino acid substituted xanthones, has become an attractive research field. The strategy of linking molecules with xanthone scaffold to peptide moieties demonstrated to be successful for the development of new antimicrobial agents. Our group has already described xanthones as promising antimicrobials, and as inhibitors of antimicrobial resistance mechanisms. Enantioselectivity studies associated with biological activities were also performed by us, and for some chiral derivatives of xanthones (CDXs) differences were found for the respective enantiomers. Herein, a small library of CDXs was synthesized and their enantiomeric purity was evaluated by chiral liquid chromatography. Enantiomeric ratio values higher than 99% were achieved. The potential of CDXs as antimicrobial agents, and their application to improve the activity of common antibiotics or to reverse bacterial mechanism of resistance were studied. In addition, to gain a better insight on how the active compounds bind to the bacterial efflux pumps, in silico studies were performed. Hit compounds were suggested and, in some cases, enantioselectivity was evident.

Keywords: antimicrobial resistance; bacterial efflux pumps; chiral; docking; enantioselectivity; xanthones