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Discovery of Potent and Fast-Acting Antimalarial Bis-1,2,4-triazines

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journal contribution
posted on 24.03.2021, 12:50 by 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
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.