Please use this identifier to cite or link to this item: http://docs.prosentient.com.au/prosentientjspui/handle/1/10434
Title: 3,3'-Disubstituted 5,5'-Bi(1,2,4-triazine) Derivatives with Potent in Vitro and in Vivo Antimalarial Activity.
Authors: Xue, Lian
Shi, Da-Hua
Harjani, Jitendra R
Huang, Fei
Beveridge, Julia G
Dingjan, Tamir
Ban, Kung
Diab, Sarah
Duffy, Sandra
Lucantoni, Leonardo
Fletcher, Sabine
Chiu, Francis C K
Blundell, Scott
Ellis, Katherine
Ralph, Stuart A
Wirjanata, Grennady
Teguh, Silvia
Noviyanti, Rintis
Chavchich, Marina
Creek, Darren
Price, Ric N
Marfurt, Jutta
Charman, Susan A
Cuellar, Matthew E
Strasser, Jessica M
Dahlin, Jayme L
Walters, Michael A
Edstein, Michael D
Avery, Vicky M
Baell, Jonathan B
Affiliation: School of Pharmaceutical Sciences , Nanjing Tech University , No. 30 South Puzhu Road , Nanjing 211816 , People's Republic of China..
Medicinal Chemistry , Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus) , 381 Royal Parade , Parkville , Victoria 3052 , Australia..
Medicinal Chemistry , Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus) , 381 Royal Parade , Parkville , Victoria 3052 , Australia..
School of Pharmaceutical Sciences , Nanjing Tech University , No. 30 South Puzhu Road , Nanjing 211816 , People's Republic of China..
Medicinal Chemistry , Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus) , 381 Royal Parade , Parkville , Victoria 3052 , Australia..
Medicinal Chemistry , Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus) , 381 Royal Parade , Parkville , Victoria 3052 , Australia..
Medicinal Chemistry , Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus) , 381 Royal Parade , Parkville , Victoria 3052 , Australia..
Medicinal Chemistry , Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus) , 381 Royal Parade , Parkville , Victoria 3052 , Australia..
Discovery Biology, Griffith Institute for Drug Discovery , Griffith University , Brisbane Innovation Park , Nathan , Queensland 4111 , Australia..
Discovery Biology, Griffith Institute for Drug Discovery , Griffith University , Brisbane Innovation Park , Nathan , Queensland 4111 , Australia..
Discovery Biology, Griffith Institute for Drug Discovery , Griffith University , Brisbane Innovation Park , Nathan , Queensland 4111 , Australia..
Centre for Drug Candidate Optimisation , Monash University (Parkville Campus) , 381 Royal Parade , Parkville , Victoria 3052 , Australia..
Centre for Drug Candidate Optimisation , Monash University (Parkville Campus) , 381 Royal Parade , Parkville , Victoria 3052 , Australia..
Drug Delivery Disposition and Dynamics , Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus) , 381 Royal Parade , Parkville , Victoria 3052 , Australia..
Bio21 Institute , The University of Melbourne , Parkville , Victoria 3052 , Australia..
Global and Tropical Health Division , Menzies School of Health Research and Charles Darwin University , Royal Darwin Hospital Campus, Rocklands Drive , Casuarina , Northern Territory 0810 , Australia..
Medicinal Chemistry , Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus) , 381 Royal Parade , Parkville , Victoria 3052 , Australia..
Eijkman Institute for Molecular Biology , Jalan Diponegoro 69 , Jakarta 10430 , Indonesia..
The Department of Drug Evaluation , Australian Defence Force Malaria and Infectious Disease Institute , Brisbane , Queensland 4052 , Australia..
Drug Delivery Disposition and Dynamics , Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus) , 381 Royal Parade , Parkville , Victoria 3052 , Australia..
Global and Tropical Health Division , Menzies School of Health Research and Charles Darwin University , Royal Darwin Hospital Campus, Rocklands Drive , Casuarina , Northern Territory 0810 , Australia.. Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine , University of Oxford , Oxford OX3 7LJ , U.K..
Global and Tropical Health Division , Menzies School of Health Research and Charles Darwin University , Royal Darwin Hospital Campus, Rocklands Drive , Casuarina , Northern Territory 0810 , Australia..
Centre for Drug Candidate Optimisation , Monash University (Parkville Campus) , 381 Royal Parade , Parkville , Victoria 3052 , Australia..
Institute for Therapeutics Discovery and Development , University of Minnesota , 717 Delaware Street SE , Minneapolis , Minnesota , United States..
Institute for Therapeutics Discovery and Development , University of Minnesota , 717 Delaware Street SE , Minneapolis , Minnesota , United States..
Department of Pathology , Brigham and Women's Hospital , 75 Francis Street , Boston , Massachusetts 02115 , United States..
Institute for Therapeutics Discovery and Development , University of Minnesota , 717 Delaware Street SE , Minneapolis , Minnesota , United States..
The Department of Drug Evaluation , Australian Defence Force Malaria and Infectious Disease Institute , Brisbane , Queensland 4052 , Australia..
Discovery Biology, Griffith Institute for Drug Discovery , Griffith University , Brisbane Innovation Park , Nathan , Queensland 4111 , Australia..
School of Pharmaceutical Sciences , Nanjing Tech University , No. 30 South Puzhu Road , Nanjing 211816 , People's Republic of China.. Medicinal Chemistry , Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus) , 381 Royal Parade , Parkville , Victoria 3052 , Australia..
Issue Date: 14-Mar-2019
Citation: Journal of medicinal chemistry 2019-03-14; 62(5): 2485-2498
Abstract: A series of 3,3'-disubstituted 5,5'-bi(1,2,4-triazine) derivatives was synthesized and screened against the erythrocytic stage of Plasmodium falciparum 3D7 line. The most potent dimer, 6k, with an IC50 (50% inhibitory concentration) of 0.008 μM, had high in vitro potency against P. falciparum lines resistant to chloroquine (W2, IC50 = 0.0047 ± 0.0011 μM) and artemisinin (MRA1240, IC50 = 0.0086 ± 0.0010 μM). Excellent ex vivo potency of 6k was shown against clinical field isolates of both P. falciparum (IC50 = 0.022-0.034 μM) and Plasmodium vivax (IC50 = 0.0093-0.031 μM) from the blood of outpatients with uncomplicated malaria. Despite 6k being cleared relatively rapidly in mice, it suppressed parasitemia in the Peters 4-day test, with a mean ED50 value (50% effective dose) of 1.47 mg kg-1 day-1 following oral administration. The disubstituted triazine dimer 6k represents a new class of orally available antimalarial compounds of considerable interest for further development.
URI: http://docs.prosentient.com.au/prosentientjspui/handle/1/10434
DOI: 10.1021/acs.jmedchem.8b01799
ORCID: http://orcid.org/0000-0001-7497-7082
http://orcid.org/0000-0001-5650-9277
http://orcid.org/0000-0003-2114-8242
Type: Journal Article
Appears in Collections:NT Health digital library

Files in This Item:
There are no files associated with this item.


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.