Novel nucleoside-based antimalarial compounds

• Published in: Bioorganic & medicinal chemistry letters Vol. 26; no. 12; pp. 2861 - 2865
• Main Authors: Zheng, Zhaoyan, Tran, Huu-Anh, Manivannan, Srinivasan, Wen, Xianghui, Kaiser, Marcel, Brun, Reto, Snyder, Floyd F., Back, Thomas G.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.06.2016; Elsevier
• Subjects: Animals; Antimalarial compounds; Antimalarials - chemical synthesis; Antimalarials - chemistry; Antimalarials - pharmacology; Cell Line; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Dose-Response Relationship, Drug; Humans; Life Sciences & Biomedicine; Malaria - drug therapy; Molecular Structure; Myoblasts - drug effects; Myoblasts - parasitology; Nucleosides; Nucleosides - chemical synthesis; Nucleosides - chemistry; Nucleosides - pharmacology; Parasitic Sensitivity Tests; Pharmacology & Pharmacy; Physical Sciences; Plasmodium falciparum; Plasmodium falciparum - drug effects; Purine salvage pathways; Rats; Science & Technology; Structure-Activity Relationship; Nucleosides; Antimalarial compounds; Purine salvage pathways; PATHWAYS; IDENTIFICATION; PHOSPHORYLASE; ENZYME-KINETICS; METABOLISM; ARTEMISININ RESISTANCE; PLASMODIUM-FALCIPARUM; PURIFICATION; ADENINE; TAUTOMERISM
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2016.04.053

P. falciparum IC50 as low as 110nM with cytotoxicity toward L6 rat myoblast cell line of 111μM and a selectivity index >1000. [Display omitted] The malaria-causing parasite Plasmodium falciparum employs a salvage pathway for the biosynthesis of nucleotides, in contrast to de novo biosynthesis that is utilized by the human host. A series of twenty-two 2-, 6- and 5′-modified adenosine ribonucleosides was synthesized, with the expectation that these compounds would generate toxic metabolites instead of active nucleotides by the pathogen, while remaining inert in host cells. Bioassays with P. falciparum (K1 strain) indicated IC50 values as low as 110nM and a selectivity index with respect to cytotoxicity toward an L6 rat myoblast cell line of >1000 for the most potent analogue.