3,3′-Disubstituted 5,5′-Bi(1,2,4-triazine) derivatives with potent in vitro and in vivo antimalarial activity
| Autor: | Sandra Duffy, Marina Chavchich, Grennady Wirjanata, Silvia Teguh, Susan A. Charman, Rintis Noviyanti, Jitendra R. Harjani, Leonardo Lucantoni, Lian Xue, Jutta Marfurt, Michael D. Edstein, Ric N. Price, Tamir Dingjan, Stuart A. Ralph, Julia G. Beveridge, Michael A. Walters, Katherine M. Ellis, Scott Blundell, Jonathan B. Baell, Darren J. Creek, Fei Huang, Sabine Fletcher, Sarah Diab, Vicky M. Avery, Jayme L. Dahlin, Francis C. K. Chiu, Kung Ban, Jessica M. Strasser, Matthew E. Cuellar, Da Hua Shi |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Plasmodium
Magnetic Resonance Spectroscopy Plasmodium vivax Drug Resistance Parasitemia Pharmacology In Vitro Techniques 01 natural sciences 03 medical and health sciences Antimalarials Mice Structure-Activity Relationship Species Specificity In vivo parasitic diseases Drug Discovery medicine Potency Animals Humans Artemisinin IC50 030304 developmental biology 0303 health sciences biology Molecular Structure Chemistry Triazines Plasmodium falciparum Chloroquine medicine.disease biology.organism_classification 0104 chemical sciences 010404 medicinal & biomolecular chemistry Molecular Medicine Ex vivo medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 62(5) |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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