Synthesis and Anti-dengue Virus Activity of 5-Ethynylimidazole-4-carboxamide (EICA) Nucleotide Prodrugs

• Published in: Chemical & pharmaceutical bulletin Vol. 70; no. 3; pp. 220 - 225
• Main Authors: Nakamura, Motoki, Uemura, Kentaro, Saito-Tarashima, Noriko, Sato, Akihiko, Orba, Yasuko, Sawa, Hirofumi, Matsuda, Akira, Maenaka, Katsumi, Minakawa, Noriaki
• Format: Journal Article
• Language: English
• Published: Japan The Pharmaceutical Society of Japan 01-03-2022; Japan Science and Technology Agency
• Subjects: 4′-thio-modification; Antiviral activity; Antiviral Agents - pharmacology; Bioactive compounds; Biological activity; Cell Line; Cell lines; Cytotoxicity; Dengue fever; dengue virus; Dengue Virus - drug effects; Drugs; Imidazole; imidazole nucleoside; Imidazoles - pharmacology; Kinases; Nucleotides; Nucleotides - pharmacology; Phosphorylation; prodrug; Prodrugs; Prodrugs - pharmacology; Toxicity; Virus Replication; Viruses; prodrug; 4′-thio-modification; antiviral activity; dengue virus; imidazole nucleoside
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.c21-01038

We previously showed that 5-ethynyl-(1-β-D-ribofuranosyl)imidazole-4-carboxamide (1; EICAR) is a potent anti-dengue virus (DENV) compound but is cytotoxic to some cell lines, while its 4-thio derivative, 5-ethynyl-(4-thio-1-β-D-ribofuranosyl)imidazole-4-carboxamide (2; 4′-thioEICAR), has less cytotoxicity but also less anti-DENV activity. Based on the hypothesis that the lower anti-DENV activity of 2 is due to reduced susceptibility to phosphorylation by cellular kinase(s), we investigated whether a monophosphate prodrug of 2 can improve its activity. Here, we first prepared two types of prodrug of 1, which revealed that the S-acyl-2-thioethyl (SATE) prodrug had stronger anti-DENV activity than the aryloxyphosphoramidate (so-called ProTide) prodrug. Based on these findings, we next prepared the SATE prodrug of 4′-thioEICAR 18. As expected, the resulting 18 showed potent anti-DENV activity, which was comparable to that of 1; however, its cytotoxicity was also increased relative to 2. Our findings suggest that prodrugs of 4′-thioribonucleoside derivatives such as EICAR (1) represent an effective approach to developing potent biologically active compounds; however, the balance between antiviral activity and cytotoxicity remains to be addressed.