Design, Synthesis, and Antiviral Evaluation of 2-Deoxy-D-Ribosides of Substituted Benzimidazoles as Potential Agents for Human Cytomegalovirus Infections
| Autor: | Ruiming Zou, Etsuko Kawashima, Leroy B. Townsend, John C. Drach, George Andrew Freeman, George W. Koszalka |
|---|---|
| Rok vydání: | 2000 |
| Předmět: |
Benzimidazole
Glycosylation Stereochemistry Cytomegalovirus Enzyme-Linked Immunosorbent Assay Nucleosides Viral Plaque Assay General Medicine Riboside Antiviral Agents Biochemistry Raney nickel Structure-Activity Relationship Lithium azide chemistry.chemical_compound chemistry Genetics Humans Simplexvirus Molecular Medicine Structure–activity relationship Benzimidazoles Amine gas treating Stereoselectivity |
| Zdroj: | Nucleosides, Nucleotides and Nucleic Acids. 19:125-153 |
| ISSN: | 1532-2335 1525-7770 |
| Popis: | Stereoselective glycosylation of 2,5,6-trichlorobenzimidazole (1b), 2-bromo-5,6-dichlorobenzimidazole (1c), 5,6-dichlorobenzimidazole (1d), 5,6-dichlorobenzimidazole-2-thione (1e), 5,6-dichloro-2-(methylthio)benzimidazole (1f), 2-(benzylthio)-5,6-dichlorobenzimidazole (1g), and 2-chloro-5,6-dimethylbenzimidazole (1h) with 2-deoxy-3,5-di-O-p-toluoyl-alpha-D-erythro-pentofuranosyl chloride was achieved to give the desired beta nucleosides 2b-h. Subsequent deprotection afforded the corresponding free beta-D-2-deoxyribosides 3b-h. The 2-methoxy derivative 3i was synthesized by the treatment of 2b with methanolic sodium methoxide. Displacement of the 2-chloro group of 2b with lithium azide followed by a removal of the protective groups gave the 2-azido-5,6-dichlorobenzimidazole derivative (5). The 2-amino derivative (6) was obtained by hydrogenolysis of 5 over Raney nickel. 5,6-Dichloro-2-isopropylamino-1-(2-deoxy-beta-D-erythro- pentofuranosyl)benzimidazole (10) was prepared using 2'-deoxyuridine (7), N-deoxyribofuranosyl transferase and 1d followed by functionalization of the C2 position. Antiviral evaluation of target compounds established that compounds 3b and 3c were active against human cytomegalovirus (HCMV) at non-cytotoxic concentrations. The activity of these 2-deoxy ribosides, however, was less than the activity of the parent riboside, 2,5,6-trichloro-1-beta-D-ribofuranosylbenzimidazole (TCRB). Compared to TCRB, 3b and 3c were somewhat more cytotoxic and active against herpes simplex virus type 1. Compounds 3d-i with other substituents in the 2-position were inactive against both viruses and non-cytotoxic. In contrast, compounds with amine substituents in the 2-position (5, 6, 10) were active against HCMV albeit less so than TCRB. These results establish that 2-deoxy-D-ribosyl benzimidazoles are less active against the DNA virus HCMV than are the corresponding D-ribosides. |
| Databáze: | OpenAIRE |
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