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

Lian Xue, Da Hua Shi, Jitendra R. Harjani, Fei Huang, Julia G. Beveridge, Tamir Dingjan, Kung Ban, Sarah Diab, Sandra Duffy, Leonardo Lucantoni, Sabine Fletcher, Francis C.K. Chiu, Scott Blundell, Katherine Ellis, Stuart A. Ralph, Grennady Wirjanata, Silvia Teguh, Rintis Noviyanti, Marina Chavchich, Darren CreekRic N. Price, Jutta Marfurt, Susan A. Charman, Matthew E. Cuellar, Jessica M. Strasser, Jayme L. Dahlin, Michael A. Walters, Michael D. Edstein, Vicky M. Avery, Jonathan B. Baell

    Research output: Contribution to journalArticle

    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 IC 50 (50% inhibitory concentration) of 0.008 μM, had high in vitro potency against P. falciparum lines resistant to chloroquine (W2, IC 50 = 0.0047 ± 0.0011 μM) and artemisinin (MRA1240, IC 50 = 0.0086 ± 0.0010 μM). Excellent ex vivo potency of 6k was shown against clinical field isolates of both P. falciparum (IC 50 = 0.022-0.034 μM) and Plasmodium vivax (IC 50 = 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 ED 50 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.

    Original languageEnglish
    Pages (from-to)2485-2498
    Number of pages14
    JournalJournal of Medicinal Chemistry
    Volume62
    Issue number5
    Early online date4 Feb 2019
    DOIs
    Publication statusPublished - 14 Mar 2019

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    Xue, L., Shi, D. H., Harjani, J. R., Huang, F., Beveridge, J. G., Dingjan, T., Ban, K., Diab, S., Duffy, S., Lucantoni, L., Fletcher, S., Chiu, F. C. K., Blundell, S., Ellis, K., Ralph, S. A., Wirjanata, G., Teguh, S., Noviyanti, R., Chavchich, M., ... Baell, J. B. (2019). 3,3′-Disubstituted 5,5′-Bi(1,2,4-triazine) Derivatives with Potent in Vitro and in Vivo Antimalarial Activity. Journal of Medicinal Chemistry, 62(5), 2485-2498. https://doi.org/10.1021/acs.jmedchem.8b01799