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A series of 3,3′-disubstituted 5,5′-bi(1,2,4-triazine) derivatives was synthesized and screened against the erythrocytic stage of Plasmodium falciparum3D7 line. The most potent dimer, 6k, with an IC50(50% inhibitory concentration) of 0.008 μM, had high in vitro potency against P. falciparumlines resistant to chloroquine (W2, IC50= 0.0047 ± 0.0011 μM) and artemisinin (MRA1240, IC50= 0.0086 ± 0.0010 μM). Excellent ex vivo potency of 6kwas 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 6kbeing cleared relatively rapidly in mice, it suppressed parasitemia in the Peters 4-day test, with a mean ED50value (50% effective dose) of 1.47 mg kg–1day–1following oral administration. The disubstituted triazine dimer 6krepresents a new class of orally available antimalarial compounds of considerable interest for further development.

Novel 3,3′-disubstituted-5,5′-bi(1,2,4-triazine) compounds with potent in vitroactivity against Plasmodium falciparumparasites were recently discovered. To improve the pharmacokinetic properties of the triazine derivatives, a new structure–activity relationship (SAR) investigation was initiated with a focus on enhancing the metabolic stability of lead compounds. These efforts led to the identification of second-generation highly potent antimalarial bis-triazines, exemplified by triazine 23, which exhibited significantly improved in vitrometabolic stability (8 and 42 μL/min/mg protein in human and mouse liver microsomes). The disubstituted triazine dimer 23was also observed to suppress parasitemia in the Peters 4-day test with a mean ED50value of 1.85 mg/kg/day and exhibited a fast-killing profile, revealing a new class of orally available antimalarial compounds of considerable interest.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

For Abstract see ChemInform Abstract in Full Text.

For Abstract see ChemInform Abstract in Full Text.

For Abstract see ChemInform Abstract in Full Text.

For Abstract see ChemInform Abstract in Full Text.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.