Design, synthesis, and antiviral activity of TCRB analogs based on imidazo[1,2-<italic>a</italic>]pyridine, pyrazolo[1,5-<italic>a</italic>]pyridine, and indole heterocycles.
Williams, John David
2003
Abstract
Human cytomegalovirus (HCMV) is an opportunistic virus which causes serious pathologies in immunocompromised populations. Although several drugs have been approved for the treatment of HCMV-related diseases, various limitations of these compounds make the development of new and improved drugs very desirable. The benzimidazole riboside 2,5,6-trichloro-1-(beta-D-ribofuranosyl)benzimidazole (TCRB) was found to be a potent and selective inhibitor of HCMV <italic>in vitro</italic>, but was degraded too quickly <italic>in vivo</italic> to be of interest as a clinical candidate. Several different strategies were used to design analogs of TCRB which would resist the glycosidic bond cleavage observed for TCRB, including the synthesis of C-nucleosides, and N-nucleosides with alternative heterocycles. A series of acyclic imidazo[1,2-<italic>a</italic>]pyridine nucleoside analogs was synthesized using the 2,6-dichloroimidazo[1,2-<italic>a</italic>]pyridine and 2,6,7-trichloroimidazo[1,2-<italic>a</italic>]pyridine heterocycles and various acyclic side-chains. Although structurally similar to other cyclic and acyclic nucleoside analogs which exhibit good antiviral activity, these analogs demonstrated very little antiviral activity. The C-nucleosides 2,5,6-trichloro-3-(beta-D-ribofuranosyl)pyrazolo[1,5-<italic> a</italic>]pyridine and 2,5,6-trichloro-3-(alpha-D-erythrofuranosyl)pyrazolo[1,5-<italic> a</italic>]pyridine are also desirable synthetic targets which would be hydrolytically stable. Many different routes to the common synthetic intermediate for this compound, 2,5,6-trichloropyrazolo[1,5-<italic>a</italic>]pyridine, were attempted. Despite a variety of synthetic approaches directed toward the synthesis of this common intermediate, none were found to be suitable for the synthesis of the desired nucleosides. Nucleosides incorporating 2,5,6-trichloroindole could also be far more stable than their TCRB congeners, because the 3-position of indole cannot be easily protonated. One indole analog of TCRB, 2,5,6-trichloro-3-formyl-l-(beta- D-ribofuranosyl)indole (FTCRI), demonstrated very potent and selective antiviral activity. A series of further modifications was pursued in an attempt to further increase the antiviral potency or decrease the cytotoxicity. Compounds modified at the indole 2-position were generally less active and more cytotoxic. Modifications made at the 3-position of the heterocycle had a wide variety of effects, depending on the nature of the changes made. Changes in the sugar moiety also produced a wide variety of biological effects, but some were distinctly more active and less toxic. 2, 5,6-Trichloro-3-formyl-1-(5-<italic>O</italic>-acetyl-beta- D-ribofuranosyl)indole and 2,5,6-trichloro-3-acetyl-1-(2-deoxy-beta- D-ribofuranosyl)indole were especially selective, with the former being much more potent than FTCRI, the latter being much less cytotoxic.Subjects
Activity Analogs Antiviral Based Design Heterocycles Imidazo[1,2-a]pyridine Indole Pyrazolo[1,5-a]pyridine Synthesis Tcrb Trichloro-1-(beta-d-ribofuranosyl)benzimidazole-2,5,6
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