Design,Synthesis, and Antiviral Evaluation of 2-Deoxy-D-Ribosides of Substituted Benzimidazoles as Potential Agents for Human Cytomegalovirus Infections |
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| Authors: | Ruiming Zou Etsuko Kawashima George A Freeman George W Koszalka John C Drach Leroy B Townsend |
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| Institution: | 1. Department of Medicinal Chemistry, College of Pharmacy;2. Department of Chemistry, College of Literature, Sciences and Arts;3. Department of Biologic and Materials Sciences , School of Dentistry, University of Michigan , Ann Arbor, MI, 48109-1065, USA;4. Gilead Sciences , 344 Lakeside Drive, Foster City, California, 94404;5. Tokyo University of Pharmacy and Life Science , 1432-1 Horinouchi, Hachioji, Tokyo, JAPAN;6. Glaxo Wellcome, Inc. , Five Moore Drive, Research Triangle Park, NC, 27709;7. Department of Biologic and Materials Sciences , School of Dentistry, University of Michigan , Ann Arbor, MI, 48109-1065, USA |
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| Abstract: | Abstract 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-α-D-erythro-pentofuranosyl chloride was achieved to give the desired β nucleosides 2b-h. Subsequent deprotection afforded the corresponding free β-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-β-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-β-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. |
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