Discovery of Potent and Fast-Acting Antimalarial Bis-1,2,4-triazines
| Autor: | Helena Barker, Amanda De Paoli, Erin Tay, Given Lee, Sandra Duffy, Susan A. Charman, Robert T. Jacobs, Jitendra R. Harjani, Longjin Zhong, Marina Chavchich, Wen Wang, Da Hua Shi, Mitch Mathiew, Stephen Brand, Vicky M. Avery, Michael D. Edstein, Jonathan B. Baell, Darren J. Creek, Daniel L. Priebbenow, David M. Shackleford, Julia G. Beveridge, Karen L. White, Elly Crighton |
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| Rok vydání: | 2021 |
| Předmět: |
Male
Plasmodium berghei Plasmodium falciparum Parasitemia Mice SCID Pharmacology 01 natural sciences Rats Sprague-Dawley 03 medical and health sciences chemistry.chemical_compound Antimalarials Structure-Activity Relationship Pharmacokinetics Parasitic Sensitivity Tests Mice Inbred NOD Drug Discovery medicine Structure–activity relationship Animals Humans 030304 developmental biology Triazine 0303 health sciences biology Molecular Structure Triazines biology.organism_classification medicine.disease In vitro 0104 chemical sciences Malaria 010404 medicinal & biomolecular chemistry chemistry Microsome Microsomes Liver Molecular Medicine Female Caco-2 Cells |
| Zdroj: | Journal of medicinal chemistry. 64(7) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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