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Discovery and Structure-Activity Relationships of Quinazolinone-2-carboxamide Derivatives as Novel Orally Efficacious Antimalarials.
Laleu, Benoît; Akao, Yuichiro; Ochida, Atsuko; Duffy, Sandra; Lucantoni, Leonardo; Shackleford, David M; Chen, Gong; Katneni, Kasiram; Chiu, Francis C K; White, Karen L; Chen, Xue; Sturm, Angelika; Dechering, Koen J; Crespo, Benigno; Sanz, Laura M; Wang, Binglin; Wittlin, Sergio; Charman, Susan A; Avery, Vicky M; Cho, Nobuo; Kamaura, Masahiro.
Afiliação
  • Laleu B; Medicines for Malaria Venture, ICC, Route de Pré-Bois 20, 1215 Geneva, Switzerland.
  • Akao Y; Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
  • Ochida A; Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
  • Duffy S; Discovery Biology, Griffith University, Brisbane Innovation Park, Don Young Road, Nathan 4111, Queensland, Australia.
  • Lucantoni L; Discovery Biology, Griffith University, Brisbane Innovation Park, Don Young Road, Nathan 4111, Queensland, Australia.
  • Shackleford DM; Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
  • Chen G; Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
  • Katneni K; Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
  • Chiu FCK; Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
  • White KL; Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
  • Chen X; WuXi AppTec (Wuhan) Company Ltd., 666 Gaoxin Avenue, Donghu New Technology Development Area, Wuhan 430075, China.
  • Sturm A; TropIQ Health Sciences, Transistorweg 5-C02, 6534 AT Nijmegen, The Netherlands.
  • Dechering KJ; TropIQ Health Sciences, Transistorweg 5-C02, 6534 AT Nijmegen, The Netherlands.
  • Crespo B; Global Health, GlaxoSmithKline R&D, Tres Cantos, 28760, Madrid, Spain.
  • Sanz LM; Global Health, GlaxoSmithKline R&D, Tres Cantos, 28760, Madrid, Spain.
  • Wang B; WuXi AppTec (Wuhan) Company Ltd., 666 Gaoxin Avenue, Donghu New Technology Development Area, Wuhan 430075, China.
  • Wittlin S; Swiss Tropical and Public Health Institute, Socinstrasse 57, 4002 Basel, Switzerland.
  • Charman SA; University of Basel, 4002 Basel, Switzerland.
  • Avery VM; Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
  • Cho N; Discovery Biology, Griffith University, Brisbane Innovation Park, Don Young Road, Nathan 4111, Queensland, Australia.
  • Kamaura M; Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
J Med Chem ; 64(17): 12582-12602, 2021 09 09.
Article em En | MEDLINE | ID: mdl-34437804
ABSTRACT
A phenotypic high-throughput screen allowed discovery of quinazolinone-2-carboxamide derivatives as a novel antimalarial scaffold. Structure-activity relationship studies led to identification of a potent inhibitor 19f, 95-fold more potent than the original hit compound, active against laboratory-resistant strains of malaria. Profiling of 19f suggested a fast in vitro killing profile. In vivo activity in a murine model of human malaria in a dose-dependent manner constitutes a concomitant benefit.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Malária Falciparum / Quinazolinonas / Antimaláricos Limite: Animals / Humans Idioma: En Revista: J Med Chem Assunto da revista: QUIMICA Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Suíça
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Malária Falciparum / Quinazolinonas / Antimaláricos Limite: Animals / Humans Idioma: En Revista: J Med Chem Assunto da revista: QUIMICA Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Suíça