title: Design, synthesis, and antiviral evaluations of 1-(substituted benzyl)-2-substituted-5,6-dichlorobenzimidazoles as nonnucleoside analogues of 2,5,6-trichloro-1-(beta-D-ribofuranosyl)benzimidazole.
abstract: We have recently reported that certain ribosylated polyhalogenated benzimidazoles are potent and selective inhibitors of HCMV replication at noncytotoxic concentrations. To extend the structure-activity relationship beyond these first-generation compounds, we alkylated 5,6-dichloro-2-substituted-benzimidazoles with either a series of substituted benzyl halides or (2-bromoethyl)benzene to obtain five series of nonnucleoside analogues. Evaluation of these compounds for activity against herpes viruses revealed that the new compounds were less active than the benzimidazole ribonucleosides against human cytomegalovirus (HCMV) and inactive against herpes simplex virus type 1 (HSV-1). However, as part of our broader antiviral testing, we found that some of these compounds were active against HIV. Comparisons of the biological data revealed that a chloro or bromo group was required at the 2-position for the best separation of activity against HIV and cytotoxicity. Evaluation of the most active compounds against drug-resistant HIV suggested that they act by a mechanism other than inhibition of reverse transcriptase.
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109-1065, USA.
authors.forename: A R
authors.initials: AR
authors.lastname: Porcari
authors.forename: R V
authors.initials: RV
authors.lastname: Devivar
authors.forename: L S
authors.initials: LS
authors.lastname: Kucera
authors.forename: J C
authors.initials: JC
authors.lastname: Drach
authors.forename: L B
authors.initials: LB
authors.lastname: Townsend
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003587:Cytomegalovirus / Q000187:drug effects / Q000254:growth & development; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D005347:Fibroblasts / Q000187:drug effects / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development; D015498:HIV-2 / Q000187:drug effects / Q000254:growth & development; D018259:Herpesvirus 1, Human / Q000187:drug effects / Q000254:growth & development; D006801:Humans; D007624:KB Cells; D008826:Microbial Sensitivity Tests; D012194:RNA-Directed DNA Polymerase / Q000096:biosynthesis; D012263:Ribonucleosides / Q000737:chemistry / Q000494:pharmacology*; D012867:Skin / Q000166:cytology / Q000187:drug effects / Q000821:virology; D013329:Structure-Activity Relationship; D010948:Viral Plaque Assay
chemical_list: C111642:2,5,6-trichloro-1-(ribofuranosyl)benzimidazole; D019380:Anti-HIV Agents; D000998:Antiviral Agents; D001562:Benzimidazoles; D012263:Ribonucleosides; D012194:RNA-Directed DNA Polymerase