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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
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.
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Journal title: Journal of medicinal chemistry
Publication Date: 2019-03-14
Type: Journal Article
DOI: 10.1021/acs.jmedchem.8b01799
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