Structure-activity relationships among 2-substituted 5,6-dichloro-, 4,6-dichloro-, and 4,5-dichloro-1-[(2-hydroxyethoxy) methyl]- and -1-[(1,3-dihydroxy-2-propoxy) methyl]benzimidazoles.
The sodium salt of 2,5,6-trichlorobenzimidazole (8a) was condensed with [2-(benzyloxy)ethoxy]-methyl chloride (9) and [1,3-bis(benzyloxy)-2-propoxy]methyl chloride (18) to provide the corresponding protected acyclic nucleosides 10a and 19a, which on debenzylation afforded 2,5,6-trichloro-1-[(2-hydroxyethoxy)methyl]benzimidazole (11a) and 2,5,6-trichloro-1-[(1,3-dihydroxy-2-propoxy)methyl] benzimidazole (20a), respectively. A similar condensation of 2,4,6-trichlorobenzimidazole (2a) and 2,4,5-trichlorobenzimidazole (7a) followed by debenzylation yielded 11b, 20b, 11c, and 20c, respectively. A nucleophilic displacement of the 2-chloro group of 11a-c and 20a-c with liquid ammonia, methylamine, dimethylamine, and thiourea furnished several interesting 2-substituted compounds in good yields, e.g., 12-14(a-e), 21-23(a-e), 15-17, and 24-26. Alkylation of the 2-thio analogs 15-17 and 24-26 with benzyl chloride furnished the 2-alkylthio acyclic nucleosides 12d-14d and 21d-23d. Desulfurization of 15 and 24 with Raney Ni furnished 5,6-dichloro-1[(2-hydroxyethoxy)methyl]benzimidazole (12e) and 5,6-dichloro-1-[1,3-dihydroxy-2-propoxy)methyl]benzimidazole (21e), respectively (acyclic analog of 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole). Similarly the dihalo compounds 13e, 14e, and 23e were prepared in moderate yields from the 2-thio analogs 16,17, and 26. Treatment of 2-bromo-5,6-dichlorobenzimidazole (8b) with 27 and 30 gave the protected acyclic compounds 28a and 31a, which on deacetylation with sodium carbonate and potassium cyanide yielded 2-bromo-5,6-dichloro-1-[(2-hydroxyethoxy)methyl]benzimidazole (29a) and 2-bromo-5,6-dichloro-1-[(1,3-dihydroxy-2-propoxy)methyl]benzimidazole (32a), respectively, in moderate yields. The 2-bromo-4,6-dichlorobenzimidazole and 2-bromo-,5-dichlorbenzimidazole analogs 29b,c and 32b,c were prepared in a similar manner. Compounds were tested for activity against human cytomegalovirus (HCMV) and herpes simplex virus type 1 (HSV-1) and for cytotoxicity. In marked contrast to the ribosylbenzimidazoles, none of the acyclic analogs were specific and potent inhibitors of HCMV. Only the 2-thiobenzyl analogs 12d, 13d, 14d, and 23d and the 2-Br analogs 32a,b were active, but activity was not well separated from cytotoxicity. The lack of specific and potent antiviral activity strongly suggests that these acyclic nucleoside analogs are not phosphorylated by HCMV or HSV-1 gene products and that the ribosylbenzimidazoles do not require phosphorylation for antiviral activity.
Saluja
S
S
Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, 48109-1065, USA.
Zou
R
R
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; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts; D018259:Herpesvirus 1, Human / Q000187:drug effects; D006801:Humans; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D012867:Skin; D013329:Structure-Activity Relationship
D000998:Antiviral Agents; D001562:Benzimidazoles; D007202:Indicators and Reagents