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

• Published in: Journal of medicinal chemistry Vol. 62; no. 5; pp. 2485 - 2498
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 14.03.2019; Amer Chemical Soc
• Subjects: Animals; Antimalarials - chemistry; Antimalarials - pharmacokinetics; Antimalarials - pharmacology; Chemistry, Medicinal; Chloroquine - pharmacology; Drug Resistance; Humans; In Vitro Techniques; Life Sciences & Biomedicine; Magnetic Resonance Spectroscopy - methods; Mice; Molecular Structure; Pharmacology & Pharmacy; Plasmodium - classification; Plasmodium - drug effects; Science & Technology; Species Specificity; Structure-Activity Relationship; Triazines - chemistry; Triazines - pharmacokinetics; Triazines - pharmacology; PREVENTION; MALARIA; ASSAY INTERFERENCE; PAINS; PLASMODIUM-FALCIPARUM
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.8b01799

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.