Synthesis, Antiviral Activity, and Mode of Action of Some 3-Substituted 2,5,6-Trichloroindole 2‘- and 5‘-Deoxyribonucleosides

• Published in: Journal of medicinal chemistry 2004-11, Vol.47 (23), p.5773-5782
• Main Authors: Williams, John D, Ptak, Roger G, Drach, John C, Townsend, Leroy B
• Format: Article
• Language: English
• Subjects: Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Biological and medical sciences; Cell Line; Cytomegalovirus - drug effects; Deoxyribonucleosides - chemical synthesis; Deoxyribonucleosides - chemistry; Deoxyribonucleosides - pharmacology; Herpes simplex virus 1; Herpesvirus 1, Human - drug effects; Human cytomegalovirus; Humans; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; Medical sciences; Molecular Conformation; Pharmacology. Drug treatments; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0400606

A series of chlorinated indole nucleosides has been synthesized and tested for activity against human cytomegalovirus (HCMV) and herpes simplex virus type-1 (HSV-1) and for cytotoxicity. The 2‘- and 5‘-deoxy derivatives of the reported 3-formyl-2,5,6-trichloro-1-(β-d-ribofuranosyl)indole (FTCRI) and 3-cyano-2,5,6-trichloro-1-(β-d-ribofuranosyl)indole (CTCRI) were synthesized by either a modification of the appropriate 3-unsubstituted sugar-modified nucleoside analogues or by a glycosylation of 3-substituted heterocycles with a protected α-chlorosugar. The modifications were guided in part by structural similarity to the corresponding series of chlorinated benzimidazole ribonucleosides and the fact that 5‘-deoxy analogues of 2,5,6-trichloro-1-(β-d-ribofuranosyl)benzimidazole (TCRB) are very active against HCMV. The 5‘-deoxy analogues of FTCRI and CTCRI were nearly as active as FTCRI and CTCRI, suggesting that the chlorinated benzimidazole nucleosides and the chlorinated indole nucleosides act in a similar manner. This hypothesis was supported by time-of-addition studies using FTCRI and by the resistance of TCRB-resistant strains of HCMV to four different 3-substituted indole ribonucleosides. The 2‘-deoxy analogues of the trichlorinated indole nucleosides also had potent antiviral activity, in contrast to decreased activity and selectivity observed for 2‘-deoxy TCRB compared to TCRB. In addition, 3-acetyl-2,5,6-trichloro-1-(2-deoxy-β-d-ribofuranosyl)indole was also active and much less cytotoxic (HCMV IC50 = 0.30 μM, HFF CC50 >100 μM) than previous analogues. None of the analogues had significant activity against HSV-1.