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; 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

doi: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

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

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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 language	English
Pages (from-to)	2485-2498
Number of pages	14
Journal	Journal of Medicinal Chemistry
Volume	62
Issue number	5
Early online date	4 Feb 2019
DOIs	https://doi.org/10.1021/acs.jmedchem.8b01799
Publication status	Published - 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

@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 = mar,

day = "14",

doi = "10.1021/acs.jmedchem.8b01799",

language = "English",

volume = "62",

pages = "2485--2498",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "5",

}

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

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

C2 - 30715882

AN - SCOPUS:85062831950

VL - 62

SP - 2485

EP - 2498

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 5

ER -

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

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