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J Med Chem. 2019 Mar 14;62(5):2485-2498. doi: 10.1021/acs.jmedchem.8b01799. Epub 2019 Mar 5.

3,3'-Disubstituted 5,5'-Bi(1,2,4-triazine) Derivatives with Potent in Vitro and in Vivo Antimalarial Activity.

Author information

1
School of Pharmaceutical Sciences , Nanjing Tech University , No. 30 South Puzhu Road , Nanjing 211816 , People's Republic of China.
2
Medicinal Chemistry , Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus) , 381 Royal Parade , Parkville , Victoria 3052 , Australia.
3
Discovery Biology, Griffith Institute for Drug Discovery , Griffith University , Brisbane Innovation Park , Nathan , Queensland 4111 , Australia.
4
Centre for Drug Candidate Optimisation , Monash University (Parkville Campus) , 381 Royal Parade , Parkville , Victoria 3052 , Australia.
5
Drug Delivery Disposition and Dynamics , Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus) , 381 Royal Parade , Parkville , Victoria 3052 , Australia.
6
Bio21 Institute , The University of Melbourne , Parkville , Victoria 3052 , Australia.
7
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.
8
Eijkman Institute for Molecular Biology , Jalan Diponegoro 69 , Jakarta 10430 , Indonesia.
9
The Department of Drug Evaluation , Australian Defence Force Malaria and Infectious Disease Institute , Brisbane , Queensland 4052 , Australia.
10
Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine , University of Oxford , Oxford OX3 7LJ , U.K.
11
Institute for Therapeutics Discovery and Development , University of Minnesota , 717 Delaware Street SE , Minneapolis , Minnesota , United States.
12
Department of Pathology , Brigham and Women's Hospital , 75 Francis Street , Boston , Massachusetts 02115 , United States.

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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