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N6-modification of 7-Deazapurine nucleoside analogues as Anti-Trypanosoma cruzi and anti-Leishmania agents: Structure-activity relationship exploration and In vivo evaluation.
Lin, Cai; Jaén Batista, Denise da Gama; Mazzeti, Ana Lia; Donola Girão, Roberson; de Oliveira, Gabriel Melo; Karalic, Izet; Hulpia, Fabian; Soeiro, Maria de Nazaré C; Maes, Louis; Caljon, Guy; Van Calenbergh, Serge.
Afiliação
  • Lin C; Laboratory for Medicinal Chemistry (Campus Heymans), Ghent University, Ottergemsesteenweg 460, B-9000, Gent, Belgium.
  • Jaén Batista DDG; Laboratório de Biologia Celular, Instituto Oswaldo Cruz (FIOCRUZ), Fundação Oswaldo Cruz, Rio de Janeiro, Avenida Brasil 4365, Manguinhos, 21040-360, Rio de Janeiro, Brazil.
  • Mazzeti AL; Laboratório de Biologia Celular, Instituto Oswaldo Cruz (FIOCRUZ), Fundação Oswaldo Cruz, Rio de Janeiro, Avenida Brasil 4365, Manguinhos, 21040-360, Rio de Janeiro, Brazil.
  • Donola Girão R; Laboratório de Biologia Celular, Instituto Oswaldo Cruz (FIOCRUZ), Fundação Oswaldo Cruz, Rio de Janeiro, Avenida Brasil 4365, Manguinhos, 21040-360, Rio de Janeiro, Brazil.
  • de Oliveira GM; Laboratório de Biologia Celular, Instituto Oswaldo Cruz (FIOCRUZ), Fundação Oswaldo Cruz, Rio de Janeiro, Avenida Brasil 4365, Manguinhos, 21040-360, Rio de Janeiro, Brazil.
  • Karalic I; Laboratory for Medicinal Chemistry (Campus Heymans), Ghent University, Ottergemsesteenweg 460, B-9000, Gent, Belgium.
  • Hulpia F; Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340, Beerse, Belgium.
  • Soeiro MNC; Laboratório de Biologia Celular, Instituto Oswaldo Cruz (FIOCRUZ), Fundação Oswaldo Cruz, Rio de Janeiro, Avenida Brasil 4365, Manguinhos, 21040-360, Rio de Janeiro, Brazil.
  • Maes L; Laboratory of Microbiology, Parasitology and Hygiene (LMPH), Infla-Med Centre of Excellence, University of Antwerp, Universiteitsplein 1, B-2610, Wilrijk, Belgium.
  • Caljon G; Laboratory of Microbiology, Parasitology and Hygiene (LMPH), Infla-Med Centre of Excellence, University of Antwerp, Universiteitsplein 1, B-2610, Wilrijk, Belgium.
  • Van Calenbergh S; Laboratory for Medicinal Chemistry (Campus Heymans), Ghent University, Ottergemsesteenweg 460, B-9000, Gent, Belgium. Electronic address: serge.vancalenbergh@ugent.be.
Eur J Med Chem ; 231: 114165, 2022 Mar 05.
Article em En | MEDLINE | ID: mdl-35144125
ABSTRACT
Chagas disease and leishmaniasis are two poverty-related neglected tropical diseases that cause high mortality and morbidity. Current treatments suffer from severe limitations and novel, safer and more effective drugs are urgently needed. Both Trypanosoma cruzi and Leishmania are auxotrophic for purines and absolutely depend on uptake and assimilation of host purines. This led us to successfully explore purine nucleoside analogues as chemotherapeutic agents against these and other kinetoplastid infections. This study extensively explored the modification of the 6-amino group of tubercidin, a natural product with trypanocidal activity but unacceptable toxicity for clinical use. We found that mono-substitution of the amine with short alkyls elicits potent and selective antitrypanosomal and antileishmanial activity. The methyl analogue 15 displayed the best in vitro activity against both T. cruzi and L. infantum and high selectivity versus host cells. Oral administration for five consecutive days in an acute Chagas disease mouse model resulted in significantly reduced peak parasitemia levels (75, 89 and 96% with 12.5, 25 and 50 mg/kg/day, respectively). as well as increased animal survival rates with the lower doses (83 and 67% for 12.5 and 25 mg/kg/day, respectively).
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Tripanossomicidas / Trypanosoma cruzi / Doença de Chagas / Leishmania Limite: Animals Idioma: En Revista: Eur J Med Chem Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Bélgica

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Tripanossomicidas / Trypanosoma cruzi / Doença de Chagas / Leishmania Limite: Animals Idioma: En Revista: Eur J Med Chem Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Bélgica