3,3′-Disubstituted 5,5′-Bi(1,2,4-triazine) derivatives with potent in vitro and in vivo antimalarial activity
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...
| المؤلفون الرئيسيون: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| التنسيق: | Journal article |
| اللغة: | English |
| منشور في: |
American Chemical Society
2019
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| _version_ | 1826282171791310848 |
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| author | Xue, L Shi, D-H Harjani, JR Huang, F Beveridge, J Dingjan, T Ban, K Diab, S Duffy, S Lucantoni, L Fletcher, S Chiu, FCK Blundell, SA Ellis, K Ralph, SA Wirjanata, G Teguh, S Noviyanti, R Chavchich, M Creek, DJ Price, R Marfurt, J Charman, SA Cuellar, M Strasser, J Dahlin, J Walters, MA Edstein, M Avery, VM Baell, JB |
| author_facet | Xue, L Shi, D-H Harjani, JR Huang, F Beveridge, J Dingjan, T Ban, K Diab, S Duffy, S Lucantoni, L Fletcher, S Chiu, FCK Blundell, SA Ellis, K Ralph, SA Wirjanata, G Teguh, S Noviyanti, R Chavchich, M Creek, DJ Price, R Marfurt, J Charman, SA Cuellar, M Strasser, J Dahlin, J Walters, MA Edstein, M Avery, VM Baell, JB |
| author_sort | Xue, L |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T00:39:49Z |
| format | Journal article |
| id | oxford-uuid:82a86e9f-6380-4981-9852-28db5664baa4 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T00:39:49Z |
| publishDate | 2019 |
| publisher | American Chemical Society |
| record_format | dspace |
| spelling | oxford-uuid:82a86e9f-6380-4981-9852-28db5664baa42022-03-26T21:39:06Z3,3′-Disubstituted 5,5′-Bi(1,2,4-triazine) derivatives with potent in vitro and in vivo antimalarial activityJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:82a86e9f-6380-4981-9852-28db5664baa4EnglishSymplectic Elements at OxfordAmerican Chemical Society2019Xue, LShi, D-HHarjani, JRHuang, FBeveridge, JDingjan, TBan, KDiab, SDuffy, SLucantoni, LFletcher, SChiu, FCKBlundell, SAEllis, KRalph, SAWirjanata, GTeguh, SNoviyanti, RChavchich, MCreek, DJPrice, RMarfurt, JCharman, SACuellar, MStrasser, JDahlin, JWalters, MAEdstein, MAvery, VMBaell, JBA 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. |
| spellingShingle | Xue, L Shi, D-H Harjani, JR Huang, F Beveridge, J Dingjan, T Ban, K Diab, S Duffy, S Lucantoni, L Fletcher, S Chiu, FCK Blundell, SA Ellis, K Ralph, SA Wirjanata, G Teguh, S Noviyanti, R Chavchich, M Creek, DJ Price, R Marfurt, J Charman, SA Cuellar, M Strasser, J Dahlin, J Walters, MA Edstein, M Avery, VM Baell, JB 3,3′-Disubstituted 5,5′-Bi(1,2,4-triazine) derivatives with potent in vitro and in vivo antimalarial activity |
| title | 3,3′-Disubstituted 5,5′-Bi(1,2,4-triazine) derivatives with potent in vitro and in vivo antimalarial activity |
| title_full | 3,3′-Disubstituted 5,5′-Bi(1,2,4-triazine) derivatives with potent in vitro and in vivo antimalarial activity |
| title_fullStr | 3,3′-Disubstituted 5,5′-Bi(1,2,4-triazine) derivatives with potent in vitro and in vivo antimalarial activity |
| title_full_unstemmed | 3,3′-Disubstituted 5,5′-Bi(1,2,4-triazine) derivatives with potent in vitro and in vivo antimalarial activity |
| title_short | 3,3′-Disubstituted 5,5′-Bi(1,2,4-triazine) derivatives with potent in vitro and in vivo antimalarial activity |
| title_sort | 3 3 disubstituted 5 5 bi 1 2 4 triazine derivatives with potent in vitro and in vivo antimalarial activity |
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