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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 μL/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.


Daniel L Priebbenow, Mitch Mathiew, Da-Hua Shi, Jitendra R Harjani, Julia G Beveridge, Marina Chavchich, Michael D Edstein, Sandra Duffy, Vicky M Avery, Robert T Jacobs, Stephen Brand, David M Shackleford, Wen Wang, Longjin Zhong, Given Lee, Erin Tay, Helena Barker, Elly Crighton, Karen L White, Susan A Charman, Amanda De Paoli, Darren J Creek, Jonathan B Baell. Discovery of Potent and Fast-Acting Antimalarial Bis-1,2,4-triazines. Journal of medicinal chemistry. 2021 Apr 08;64(7):4150-4162

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PMID: 33759519

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