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

Basic Information

ID: ALA4808169

Journal: J Med Chem

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

Authors: Priebbenow DL, Mathiew M, Shi DH, Harjani JR, Beveridge JG, Chavchich M, Edstein MD, Duffy S, Avery VM, Jacobs RT, Brand S, Shackleford DM, Wang W, Zhong L, Lee G, Tay E, Barker H, Crighton E, White KL, Charman SA, De Paoli A, Creek DJ, Baell JB.

Abstract: 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.

CiteXplore: 33759519

DOI: 10.1021/acs.jmedchem.1c00044

Patent ID: ┄