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

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.

• Authors: 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
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 64 Issue 7 Pg. 4150-4162 (04 08 2021) ISSN: 1520-4804 [Electronic] United States
• PMID: 33759519 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antimalarials
• Triazines

Topics

• Animals
• Antimalarials (chemical synthesis, pharmacokinetics, therapeutic use)
• Caco-2 Cells
• Female
• Humans
• Malaria (drug therapy)
• Male
• Mice, Inbred NOD
• Mice, SCID
• Microsomes, Liver (drug effects)
• Molecular Structure
• Parasitic Sensitivity Tests
• Plasmodium berghei (drug effects)
• Plasmodium falciparum (drug effects)
• Rats, Sprague-Dawley
• Structure-Activity Relationship
• Triazines (chemical synthesis, pharmacokinetics, therapeutic use)
• Mice
• Rats