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