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 Creek & 10 others Ric 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 journalArticleResearchpeer-review

    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

    Fingerprint

    Antimalarials
    Plasmodium falciparum
    Plasmodium vivax
    Triazines
    Parasitemia
    Chloroquine
    Inhibitory Concentration 50
    Malaria
    Oral Administration
    Outpatients
    1,2,4-triazine
    In Vitro Techniques

    Cite this

    Xue, L., Shi, D. H., Harjani, J. R., Huang, F., Beveridge, J. G., Dingjan, T., ... 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
    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. / 3,3′-Disubstituted 5,5′-Bi(1,2,4-triazine) Derivatives with Potent in Vitro and in Vivo Antimalarial Activity. In: Journal of Medicinal Chemistry. 2019 ; Vol. 62, No. 5. pp. 2485-2498.
    @article{8b272c144233418b9276a497f521de64,
    title = "3,3′-Disubstituted 5,5′-Bi(1,2,4-triazine) Derivatives with Potent in Vitro and in Vivo Antimalarial Activity",
    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.",
    author = "Lian Xue and Shi, {Da Hua} and Harjani, {Jitendra R.} and Fei Huang and Beveridge, {Julia G.} and Tamir Dingjan and Kung Ban and Sarah Diab and Sandra Duffy and Leonardo Lucantoni and Sabine Fletcher and Chiu, {Francis C.K.} and Scott Blundell and Katherine Ellis and Ralph, {Stuart A.} and Grennady Wirjanata and Silvia Teguh and Rintis Noviyanti and Marina Chavchich and Darren Creek and Price, {Ric N.} and Jutta Marfurt and Charman, {Susan A.} and Cuellar, {Matthew E.} and Strasser, {Jessica M.} and Dahlin, {Jayme L.} and Walters, {Michael A.} and Edstein, {Michael D.} and Avery, {Vicky M.} and Baell, {Jonathan B.}",
    year = "2019",
    month = "3",
    day = "14",
    doi = "10.1021/acs.jmedchem.8b01799",
    language = "English",
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    pages = "2485--2498",
    journal = "Journal of Medicinal Chemistry",
    issn = "0022-2623",
    publisher = "American Chemical Society",
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    Xue, L, Shi, DH, Harjani, JR, Huang, F, Beveridge, JG, Dingjan, T, Ban, K, Diab, S, Duffy, S, Lucantoni, L, Fletcher, S, Chiu, FCK, Blundell, S, Ellis, K, Ralph, SA, Wirjanata, G, Teguh, S, Noviyanti, R, Chavchich, M, Creek, D, Price, RN, Marfurt, J, Charman, SA, Cuellar, ME, Strasser, JM, Dahlin, JL, Walters, MA, Edstein, MD, Avery, VM & Baell, JB 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, vol. 62, no. 5, pp. 2485-2498. https://doi.org/10.1021/acs.jmedchem.8b01799

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

    In: Journal of Medicinal Chemistry, Vol. 62, No. 5, 14.03.2019, p. 2485-2498.

    Research output: Contribution to journalArticleResearchpeer-review

    TY - JOUR

    T1 - 3,3′-Disubstituted 5,5′-Bi(1,2,4-triazine) Derivatives with Potent in Vitro and in Vivo Antimalarial Activity

    AU - Xue, Lian

    AU - Shi, Da Hua

    AU - Harjani, Jitendra R.

    AU - Huang, Fei

    AU - Beveridge, Julia G.

    AU - Dingjan, Tamir

    AU - Ban, Kung

    AU - Diab, Sarah

    AU - Duffy, Sandra

    AU - Lucantoni, Leonardo

    AU - Fletcher, Sabine

    AU - Chiu, Francis C.K.

    AU - Blundell, Scott

    AU - Ellis, Katherine

    AU - Ralph, Stuart A.

    AU - Wirjanata, Grennady

    AU - Teguh, Silvia

    AU - Noviyanti, Rintis

    AU - Chavchich, Marina

    AU - Creek, Darren

    AU - Price, Ric N.

    AU - Marfurt, Jutta

    AU - Charman, Susan A.

    AU - Cuellar, Matthew E.

    AU - Strasser, Jessica M.

    AU - Dahlin, Jayme L.

    AU - Walters, Michael A.

    AU - Edstein, Michael D.

    AU - Avery, Vicky M.

    AU - Baell, Jonathan B.

    PY - 2019/3/14

    Y1 - 2019/3/14

    N2 - 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.

    AB - 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.

    UR - http://www.scopus.com/inward/record.url?scp=85062831950&partnerID=8YFLogxK

    U2 - 10.1021/acs.jmedchem.8b01799

    DO - 10.1021/acs.jmedchem.8b01799

    M3 - Article

    VL - 62

    SP - 2485

    EP - 2498

    JO - Journal of Medicinal Chemistry

    JF - Journal of Medicinal Chemistry

    SN - 0022-2623

    IS - 5

    ER -