Aminoquinolones and Their Benzoquinone Dimer Hybrids as Modulators of Prion Protein Conversion

• Published in: Molecules (Basel, Switzerland) Vol. 27; no. 22; p. 7935
• Main Authors: Costa, Amanda Rodrigues Pinto, Muxfeldt, Marcelly, Boechat, Fernanda da Costa Santos, de Souza, Maria Cecília Bastos Vieira, Silva, Jerson Lima, de Moraes, Marcela Cristina, Rangel, Luciana Pereira, Vieira, Tuane Cristine Ramos Gonçalves, Batalha, Pedro Netto
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 16.11.2022; MDPI
• Subjects: Aggregates; Benzoquinone; Benzoquinones - pharmacology; Biocompatibility; Conversion; Cytotoxicity; Humans; Hybrids; Neuromodulation; oxoquinoline; Pathogenesis; Polymers; prion; Prion Diseases - metabolism; Prion protein; Prion Proteins; Prions; Prions - chemistry; Proteins; quinolone; Quinolones; Quinone; scrapie; Temperature; Translocation, Genetic; Transmissible spongiform encephalopathy; Brazil; quinolone; prion; scrapie; oxoquinoline; quinone
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules27227935

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-PrP -in its infectious isoform-PrP -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 ( ) and 2,5-dichloro-3,6-bis((1-benzyl-3-carboxy-4-quinolone-6-yl)amino)-1,4-benzoquinone ( ), 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.