Effect of Indole-Containing Pyrazino[2,1-<i>b</i>]quinazoline-3,6-diones in the Virulence of Resistant Bacteria
Mariana C. Almeida,
Nikoletta Szemerédi,
Fernando Durães,
Solida Long,
Diana I. S. P. Resende,
Paulo Martins da Costa,
Madalena Pinto,
Gabriella Spengler,
Emília Sousa
Affiliations
Mariana C. Almeida
Laboratório de Química Orgânica e Farmacêutica, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal
Nikoletta Szemerédi
Department of Medical Microbiology, Albert Szent-Gyorgyi Health Center and Albert Szent-Gyorgyi Medical School, University of Szeged, Semmelweis utca 6, 6725 Szeged, Hungary
Fernando Durães
Laboratório de Química Orgânica e Farmacêutica, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal
Solida Long
Laboratório de Química Orgânica e Farmacêutica, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal
Diana I. S. P. Resende
Laboratório de Química Orgânica e Farmacêutica, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal
Paulo Martins da Costa
CIIMAR––Centro Interdisciplinar de Investigação Marinha e Ambiental, Terminal de Cruzeiros do Porto de Leixões, 4450-208 Matosinhos, Portugal
Madalena Pinto
Laboratório de Química Orgânica e Farmacêutica, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal
Gabriella Spengler
Department of Medical Microbiology, Albert Szent-Gyorgyi Health Center and Albert Szent-Gyorgyi Medical School, University of Szeged, Semmelweis utca 6, 6725 Szeged, Hungary
Emília Sousa
Laboratório de Química Orgânica e Farmacêutica, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal
Drug resistance is rising to alarming levels, constituting one of the major threats to global health. The overexpression of efflux pumps and the formation of biofilms constitute two of the most common resistance mechanisms, favoring the virulence of bacteria. Therefore, the research and development of effective antimicrobial agents that can also counteract resistance mechanisms are extremely important. Pyrazino[2,1-b]quinazoline-3,6-diones, from marine and terrestrial organisms and simpler synthetic analogues, were recently disclosed by us as having relevant antimicrobial properties. In this study, using a multi-step approach, it was possible to synthesize new pyrazino[2,1-b]quinazoline-3,6-diones focusing on compounds with fluorine substituents since, to the best of our knowledge, the synthesis of fluorinated fumiquinazoline derivatives had not been attempted before. The new synthesized derivatives were screened for antibacterial activity and, along with previously synthetized pyrazino[2,1-b]quinazoline-3,6-diones, were characterized for their antibiofilm and efflux-pump-inhibiting effects against representative bacterial species and relevant resistant clinical strains. Several compounds showed relevant antibacterial activity against the tested Gram-positive bacterial species with MIC values in the range of 12.5–77 μM. Furthermore, some derivatives showed promising results as antibiofilm agents in a crystal violet assay. The results of the ethidium bromide accumulation assay suggested that some compounds could potentially inhibit bacterial efflux pumps.
