期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 64, 期 7, 页码 4150-4162出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c00044
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资金
- Australian Research Council [DE200100949]
- National Health and Medical Research Council of Australia (NHMRC) [1030704, 1080146, 1020411, 1117602]
- NHMRC Synergy grant [1185354]
- Therapeutic Innovation Australia (TIA)
- Australian Government through the National Collaborative Research Infrastructure Strategy (NCRIS) program
- Australian Research Council [DE200100949] Funding Source: Australian Research Council
- National Health and Medical Research Council of Australia [1185354, 1080146] Funding Source: NHMRC
A series of novel 3,3'-disubstituted-5,5'-bi(1,2,4-triazine) compounds with potent in vitro activity against Plasmodium falciparum parasites were recently discovered. The new structure-activity relationship investigation led to the identification of second-generation highly potent antimalarial bis-triazines, with improved in vitro metabolic stability and a fast-killing profile. This new class of orally available antimalarial compounds is of considerable interest.
Novel 3,3'-disubstituted-5,5'-bi(1,2,4-triazine) compounds with potent in vitro activity against Plasmodium falciparum parasites 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 vitro metabolic stability (8 and 42 mu L/min/mg protein in human and mouse liver microsomes). The disubstituted triazine dimer 23 was also observed to suppress parasitemia in the Peters 4-day test with a mean ED50 value of 1.85 mg/kg/day and exhibited a fast-killing profile, revealing a new class of orally available antimalarial compounds of considerable interest.
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