Design, Synthesis, and Biological Evaluation of Tricyclic Nucleosides (Dimensional Probes) as Analogues of Certain Antiviral Polyhalogenated Benzimidazole Ribonucleosides

• Published in: Journal of medicinal chemistry 2000-06, Vol.43 (12), p.2430-2437
• Main Authors: Zhu, Zhijian, Lippa, Blaise, Drach, John C, Townsend, Leroy B
• Format: Article
• Language: English
• Subjects: 2,5,6-Trichloro-1-(^b-D-ribofuranosyl)benzimidazole; 2-Bromo-5,6-dichloro-1-(^b-D-ribofuranosyl)benzimidazole; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Benzimidazoles - chemical synthesis; Benzimidazoles - chemistry; Benzimidazoles - pharmacology; Biological and medical sciences; Cell Division - drug effects; Cell Line; Cytomegalovirus - drug effects; Enzyme-Linked Immunosorbent Assay; Herpes simplex virus 1; Herpesvirus 1, Human - drug effects; Human cytomegalovirus; Humans; Imidazoles - chemical synthesis; Imidazoles - chemistry; Imidazoles - pharmacology; Inhibitory Concentration 50; Medical sciences; Pharmacology. Drug treatments; Quinolines - chemical synthesis; Quinolines - chemistry; Quinolines - pharmacology; Ribonucleosides - chemical synthesis; Ribonucleosides - chemistry; Ribonucleosides - pharmacology; Structure-Activity Relationship; Viral Plaque Assay
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm990290y

The polyhalogenated benzimidazole nucleosides 2,5,6-trichloro-1-(β-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-(β-d-ribofuranosyl)naphtho[2,3-d]imidazoles and the N1- and N3-ribonucleosides of 2-substituted 6,7-dichloroimidazo[4,5-b]quinolines were prepared. The nucleosides 6,7-dichloro-1-(β-d-ribofuranosyl)imidazo[4,5-b]quinolin-2-one and 6,7-dichloro-3-(β-d-ribofuranosyl)imidazo[4,5-b]quinolin-2-one were selected and used as the key synthetic intermediates in the imidazo[4,5-b]quinoline 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.