Design, synthesis, and biological evaluation of tricyclic nucleosides (dimensional probes) as analogues of certain antiviral polyhalogenated benzimidazole ribonucleosides.
The polyhalogenated benzimidazole nucleosides 2,5, 6-trichloro-1-(beta-D-ribofuranosyl)benzimidazole (TCRB) and the 2-bromo analogue (BDCRB) were synthesized in our laboratory and established as potent and selective inhibitors of human cytomegalovirus (HCMV) with a novel mode of action. In an effort to study the behavior of the key substructure in a dimensionally extended manner and probe the spatial limitation of the target enzyme(s), a series of 2-substituted 6, 7-dichloro-1-(beta-D-ribofuranosyl)naphtho¿2,3-dĭmidazoles and the N1- and N3-ribonucleosides of 2-substituted 6,7-dichloroimidazo¿4, 5-bquinolines were prepared. The nucleosides 6, 7-dichloro-1-(beta-D-ribofuranosyl)imidazo¿4,5-bquinolin-2-one and 6,7-dichloro-3-(beta-D-ribofuranosyl)imidazo¿4,5-bquinolin-2-one were selected and used as the key synthetic intermediates in the imidazo¿4,5-bquinoline series. Evaluation of the compounds for activity against HCMV and herpes simplex virus type 1 revealed that the trichloro analogues of TCRB (2a, 3a) were nearly as active against HCMV as TCRB but were more cytotoxic. The results suggest that extending the heterocycle of TCRB affected the affinity for the HCMV target only slightly but increased the affinity for cellular enzymes.
Zhu
Z
Z
Department of Chemistry, College of Literature, Sciences, and Arts, University of Michigan, Ann Arbor, Michigan 48109-1065, USA.
Lippa
B
B
Drach
J C
JC
Townsend
L B
LB
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; D002460:Cell Line; D003587:Cytomegalovirus / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D018259:Herpesvirus 1, Human / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012263:Ribonucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D010948:Viral Plaque Assay
D000998:Antiviral Agents; D001562:Benzimidazoles; D007093:Imidazoles; D011804:Quinolines; D012263:Ribonucleosides