Aminoquinolones and Their Benzoquinone Dimer Hybrids as Modulators of Prion Protein Conversion
Amanda Rodrigues Pinto Costa,
Marcelly Muxfeldt,
Fernanda da Costa Santos Boechat,
Maria Cecília Bastos Vieira de Souza,
Jerson Lima Silva,
Marcela Cristina de Moraes,
Luciana Pereira Rangel,
Tuane Cristine Ramos Gonçalves Vieira,
Pedro Netto Batalha
Affiliations
Amanda Rodrigues Pinto Costa
Instituto de Química, Universidade Federal Fluminense, Niterói 24020-141, RJ, Brazil
Marcelly Muxfeldt
Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
Fernanda da Costa Santos Boechat
Instituto de Química, Universidade Federal Fluminense, Niterói 24020-141, RJ, Brazil
Maria Cecília Bastos Vieira de Souza
Instituto de Química, Universidade Federal Fluminense, Niterói 24020-141, RJ, Brazil
Jerson Lima Silva
Instituto de Bioquímica Médica Leopoldo de Meis, Instituto Nacional de Ciência e Tecnologia de Biologia Estrutural e Bioimagem, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
Marcela Cristina de Moraes
Instituto de Química, Universidade Federal Fluminense, Niterói 24020-141, RJ, Brazil
Luciana Pereira Rangel
Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
Tuane Cristine Ramos Gonçalves Vieira
Instituto de Bioquímica Médica Leopoldo de Meis, Instituto Nacional de Ciência e Tecnologia de Biologia Estrutural e Bioimagem, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
Pedro Netto Batalha
Instituto de Química, Universidade Federal Fluminense, Niterói 24020-141, RJ, Brazil
Prion Diseases or Transmissible Spongiform Encephalopathies are neurodegenerative conditions associated with a long incubation period and progressive clinical evolution, leading to death. Their pathogenesis is characterized by conformational changes of the cellular prion protein—PrPC—in its infectious isoform—PrPSc—which can form polymeric aggregates that precipitate in brain tissues. Currently, there are no effective treatments for these diseases. The 2,5-diamino-1,4-benzoquinone structure is associated with an anti-prion profile and, considering the biodynamic properties associated with 4-quinolones, in this work, 6-amino-4-quinolones derivatives and their respective benzoquinone dimeric hybrids were synthesized and had their bioactive profile evaluated through their ability to prevent prion conversion. Two hybrids, namely, 2,5-dichloro-3,6-bis((3-carboxy-1-pentyl-4-quinolone-6-yl)amino)-1,4-benzoquinone (8e) and 2,5-dichloro-3,6-bis((1-benzyl-3-carboxy-4-quinolone-6-yl)amino)-1,4-benzoquinone (8f), stood out for their prion conversion inhibition ability, affecting the fibrillation process in both the kinetics—with a shortening of the lag phase—and thermodynamics and their ability to inhibit the formation of protein aggregates without significant cytotoxicity at ten micromolar.
