Synthesis and antiviral activity of novel erythrofuranosyl imidazo[1,2-a]pyridine C-nucleosides constructed via palladium coupling of iodoimidazo[1,2-a]pyridines and dihydrofuran.
2,5,6-Trichloro-1-(beta-d-ribofuranosyl)benzimidazole (TCRB) and certain analogues have shown significant activity against human cytomegalovirus. The metabolic instability of the glycosidic linkage in TCRB prompted us to synthesize the structurally similar imidazo[1,2-a]pyridine erythrofuranosyl C-nucleosides. As an approach to the synthesis of polychlorinated imidazo[1,2-a]pyridine C-3-erythrofuranosides, a palladium-based methodology for coupling 2,3-dihydrofuran with chlorinated 3-iodoimidazo[1,2-a]pyridines was developed and optimized to give 80-90% yields of 2,6-dichloro- and 2,6,7-trichloro-3-(2,3-dideoxy-2,3-didehydro-d/l-erythrofuranosyl)imidazo[1,2-a]pyridine. Dihydroxylation of these didehydro derivatives with osmium tetroxide or with AD-mix alpha gave a mixture of erythrofuranosyl C-nucleosides that were separated by standard and then chiral chromatography. When screened for anti-HCMV and HSV-1 activity, the alpha-d anomer of 2,6,7-trichloro-3-(erythrofuranosyl)imidazo[1,2-a]pyridine proved to be the most active member of the series, while the beta-anomers all proved to be inactive.
Gudmundsson
Kristjan S
KS
Department of Medicinal Chemistry, College of Pharmacy, The University of Michigan, Ann Arbor 48019-1065, USA.
Williams
John D
JD
Drach
John C
JC
Townsend
Leroy B
LB
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002384:Catalysis; D002460:Cell Line; D003587:Cytomegalovirus / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005663:Furans / Q000737:chemistry*; D018259:Herpesvirus 1, Human / Q000187:drug effects; D006801:Humans; D009705:Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010165:Palladium; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D010948:Viral Plaque Assay
C473675:2,6,7-trichloro-3-(erythrofuranosyl)imidazo(1,2-a)pyridine; D000998:Antiviral Agents; D005663:Furans; D009705:Nucleosides; D011725:Pyridines; D010165:Palladium