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Discovery of Potent and Fast-Acting Antimalarial Bis-1,2,4-triazines.
Priebbenow, Daniel L; Mathiew, Mitch; Shi, Da-Hua; Harjani, Jitendra R; Beveridge, Julia G; Chavchich, Marina; Edstein, Michael D; Duffy, Sandra; Avery, Vicky M; Jacobs, Robert T; Brand, Stephen; Shackleford, David M; Wang, Wen; Zhong, Longjin; Lee, Given; Tay, Erin; Barker, Helena; Crighton, Elly; White, Karen L; Charman, Susan A; De Paoli, Amanda; Creek, Darren J; Baell, Jonathan B.
Afiliación
  • Priebbenow DL; School of Chemistry, The University of Melbourne, Parkville, VIC 3010, Australia.
  • Mathiew M; Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, VIC 3052, Australia.
  • Shi DH; Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, VIC 3052, Australia.
  • Harjani JR; Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, VIC 3052, Australia.
  • Beveridge JG; Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, VIC 3052, Australia.
  • Chavchich M; The Department of Drug Evaluation, Australian Defence Force Malaria and Infectious Disease Institute, Brisbane, QLD 4051, Australia.
  • Edstein MD; The Department of Drug Evaluation, Australian Defence Force Malaria and Infectious Disease Institute, Brisbane, QLD 4051, Australia.
  • Jacobs RT; Medicines for Malaria Venture (MMV), P.O. Box 1826, Route de Pré-Bois 20, CH-1215 Geneva, Switzerland.
  • Brand S; Medicines for Malaria Venture (MMV), P.O. Box 1826, Route de Pré-Bois 20, CH-1215 Geneva, Switzerland.
  • Shackleford DM; Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, VIC 3052, Australia.
  • Wang W; Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, VIC 3052, Australia.
  • Zhong L; Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, VIC 3052, Australia.
  • Lee G; Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, VIC 3052, Australia.
  • Tay E; Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, VIC 3052, Australia.
  • Barker H; Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, VIC 3052, Australia.
  • Crighton E; Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, VIC 3052, Australia.
  • White KL; Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, VIC 3052, Australia.
  • Charman SA; Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, VIC 3052, Australia.
  • De Paoli A; Drug Delivery Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, VIC 3052, Australia.
  • Creek DJ; Drug Delivery Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, VIC 3052, Australia.
  • Baell JB; Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, VIC 3052, Australia.
J Med Chem ; 64(7): 4150-4162, 2021 04 08.
Article en En | MEDLINE | ID: mdl-33759519
Novel 3,3'-disubstituted-5,5'-bi(1,2,4-triazine) compounds with potent in vitro activity against Plasmodium falciparum parasites were recently discovered. To improve the pharmacokinetic properties of the triazine derivatives, a new structure-activity relationship (SAR) investigation was initiated with a focus on enhancing the metabolic stability of lead compounds. These efforts led to the identification of second-generation highly potent antimalarial bis-triazines, exemplified by triazine 23, which exhibited significantly improved in vitro metabolic stability (8 and 42 µL/min/mg protein in human and mouse liver microsomes). The disubstituted triazine dimer 23 was also observed to suppress parasitemia in the Peters 4-day test with a mean ED50 value of 1.85 mg/kg/day and exhibited a fast-killing profile, revealing a new class of orally available antimalarial compounds of considerable interest.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Triazinas / Malaria / Antimaláricos Límite: Animals / Female / Humans / Male Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2021 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Triazinas / Malaria / Antimaláricos Límite: Animals / Female / Humans / Male Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2021 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Estados Unidos