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Predicate | Object |
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
5
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pubmed:dateCreated |
1997-4-17
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pubmed:abstractText |
2-Chloro-5,6-difluorobenzimidazole (8) was prepared from 4,5-difluoro-2-nitroaniline (5) via successive reduction, cyclization, and diazotization reactions. 2-Chloro-5,6-dibromobenzimidazole (10) was obtained by a direct bromination of 2-chlorobenzimidazole (9) with bromine-water. 2-Chloro-5,6-diiodobenzimidazole (15) was synthesized by a stepwise transformation of the nitro functions of 2-chloro-5,6-dinitrobenzimidazole (11) into iodo groups via diazotization reactions. Ribosylation of 8, 10, and 15 gave the respective beta nucleosides 16a-c as the major products along with a small amount of the alpha anomers 17a-c. Deprotection of 16a-c afforded the corresponding free beta nucleosides 2-chloro-5,6-difluoro-1-beta-D-ribofuranosylbenzimidazole (2), 2-chloro-5,6-dibromo-1-beta-D-ribofuranosylbenzimidazole (3), and 2-chloro-5,6-diiodo-1-beta-D-ribofuranosylbenzimidazole (4). Similar deprotection of the alpha anomers (17a-c) resulted in a removal of the acetyl protecting groups and a concomitant cyclization to give the 2,2'-O-cyclonucleosides (18a-c). Most of the benzimidazole heterocycles, but not the difluoro analog, were active against human cytomegalovirus (HCMV) (IC50's = 3-40 microM) and herpes simplex virus type 1 (HSV-1) (IC50's = 50-90 microM). This activity, however, was not well separated from cytotoxicity, IC50's = 10-100 microM. The corresponding unsubstituted, the 5,6-dimethyl, and the 5,6-difluoro ribonucleosides (19, 20, and 2, respectively), were inactive against both viruses. Similar to the previously reported 2,5,6-trichloro analog (TCRB), the 5,6-dibromo ribonucleoside 3 was active against HCMV (IC50 approximately 4 microM) but more cytotoxic than TCRB. The 5,6-diiodo analog 4 also was active (IC50 approximately 2 microM) but more cytotoxic (IC50 = 10-20 microM) than either 3 or TCRB. The cyclonucleosides were inactive against both viruses and not cytotoxic, or slightly active with corresponding cytotoxicity. The order of activity against HCMV of the dihalobenzimidazole ribonucleosides was I approximately equal to Br approximately equal to CI > > F > H = CH3. The order of cytotoxicity among the most active compounds, however, was I > Br > Cl, thereby establishing that TCRB had the best antiviral properties.
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pubmed:grant | |
pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical | |
pubmed:status |
MEDLINE
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pubmed:month |
Feb
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pubmed:issn |
0022-2623
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pubmed:author | |
pubmed:issnType |
Print
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pubmed:day |
28
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pubmed:volume |
40
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
811-8
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pubmed:dateRevised |
2007-11-14
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pubmed:meshHeading |
pubmed-meshheading:9057868-Antiviral Agents,
pubmed-meshheading:9057868-Benzimidazoles,
pubmed-meshheading:9057868-Cell Division,
pubmed-meshheading:9057868-Cell Line,
pubmed-meshheading:9057868-Cytomegalovirus,
pubmed-meshheading:9057868-Cytomegalovirus Infections,
pubmed-meshheading:9057868-Drug Design,
pubmed-meshheading:9057868-Humans,
pubmed-meshheading:9057868-KB Cells,
pubmed-meshheading:9057868-Magnetic Resonance Spectroscopy,
pubmed-meshheading:9057868-Molecular Structure,
pubmed-meshheading:9057868-Ribonucleosides,
pubmed-meshheading:9057868-Simplexvirus
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pubmed:year |
1997
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pubmed:articleTitle |
Design, synthesis, and antiviral evaluation of 2-chloro-5,6-dihalo-1-beta-D-ribofuranosylbenzimidazoles as potential agents for human cytomegalovirus infections.
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pubmed:affiliation |
Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor 48109-1065, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't
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