Synthesis and biological activity of 5,6-dinitro derivatives of benzimidazole

Chermova, E. Yu.; Mokrushina, G. A.; Чупахин, О. Н.; Kotovskaya, S. K.; Il'enko, V. I.; Andreeva, O. T.; Бореко, Е. И.; Vladyko, G. V.; Korobchenko, L. V.; Garagulya, A. D.; Dukhovnaya, V. M.

doi:10.1007/bf00766366

Cited by 6 publications

(7 citation statements)

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“…The introduction of iodine atoms into specific positions of the benzimidazole moiety was accomplished via stepwise diazotization and replacement reactions. Thus, the treatment of 2-chloro-5,6-dinitrobenzimidazole ( 11 ) with iron powder in acetic acid effected a selective reduction of only one of the nitro groups and gave the 5(6)-amino-6(5)-nitro derivative 12 . Diazotization of the amino group and subsequent replacement with potassium iodide afforded the corresponding 5(6)-iodo-6(5)-nitro derivative 13 .…”

Section: Resultsmentioning

confidence: 99%

“…A mixture of 2-chloro-5,6-dinitrobenzimidazole 23 (11, 1.213 g, 5.0 mmol) and iron powder (1.398 g, 25 mmol) in AcOH (50 mL) was stirred at room temperature for 4 h. The reaction mixture was diluted with 100 mL of EtOAc and filtered, and the solid was washed with portions of EtOAc (∼100 mL). The filtrate and washings were combined and washed with H2O (100 mL × 3).…”

Section: (6)-amino-2-chloro-6(5)-nitrobenzimidazole (12)mentioning

confidence: 99%

“…The mother liquor was evaporated to dryness and the residue was triturated with H2O (10 mL × 3) and then recrystallized from MeOH/Et2O (diffusion) to give an additional 0.084 g of 18b as white crystals. The total yield of 18b was 0.224 g (85%): mp 140-160 °C (melted slowly over a large range of temperature); HRMS (EI) m/z 403.8995 (26, M + ) 403.9007); 1 H NMR (DMSO-d6) δ 7.88 (s, 1, 7-H), 7.80 (s, 1, 4-H), 6.52 (d, 1, 1′-H, J1′-2′ ) 5.0 Hz), 5.78 (d, 1, 3′-OH, J3′-3′OH ) 7.0 Hz), 5.74 (t, 1, 2′-H, J2′-3′ ) 5.5 Hz), 4.84 (t, 1, 5′-OH, J5′-5′OH ) 5.0 Hz), 4.08 (m, 1, 3′-H, J3′-4′ ) 9.0 Hz), 3.69 (m, 1, 5′-H, J4′-5′ ) 0.5 Hz, J5′-5′′ ) 11.5 Hz), 3.49 (m, 2, 4′-H and 5′′-H, J4′-5′′ ) 5.0 Hz); 13 23 (19, 0.57 g, 2 mmol) in H2O (50 mL) was added dropwise 50 mL of Br2/H2O (saturated at 20 °C) over a period of 30 min. After the addition was complete, stirring was continued at room temperature for 3 h. The reaction mixture was allowed to stand in an ice-H2O bath for 30 min and then filtered.…”

Section: 6-difluoro-1-r-d-ribofuranosylbenzimidazole 22′-o-cyclonucle...mentioning

confidence: 99%

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Design, Synthesis, and Antiviral Evaluation of 2-Chloro-5,6-dihalo-1-β-d-ribofuranosylbenzimidazoles as Potential Agents for Human Cytomegalovirus Infections

1997

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2-Chloro-5,6-difluorobenzimidazole (8) was prepared from 4,5-difluoro-2-nitroaniline (5) via successive reduction, cyclization, and diazotization reactions. 2-Chloro-5,6-dibromobenzimidazole (10) was obtained by a direct bromination of 2-chlorobenzimidazole (9) with bromine-water. 2-Chloro-5,6-diiodobenzimidazole (15) was synthesized by a stepwise transformation of the nitro functions of 2-chloro-5,6-dinitrobenzimidazole (11) into iodo groups via diazotization reactions. Ribosylation of 8, 10, and 15 gave the respective beta nucleosides 16a-c as the major products along with a small amount of the alpha anomers 17a-c. Deprotection of 16a-c afforded the corresponding free beta nucleosides 2-chloro-5,6-difluoro-1-beta-D-ribofuranosylbenzimidazole (2), 2-chloro-5,6-dibromo-1-beta-D-ribofuranosylbenzimidazole (3), and 2-chloro-5,6-diiodo-1-beta-D-ribofuranosylbenzimidazole (4). Similar deprotection of the alpha anomers (17a-c) resulted in a removal of the acetyl protecting groups and a concomitant cyclization to give the 2,2'-O-cyclonucleosides (18a-c). Most of the benzimidazole heterocycles, but not the difluoro analog, were active against human cytomegalovirus (HCMV) (IC50's = 3-40 microM) and herpes simplex virus type 1 (HSV-1) (IC50's = 50-90 microM). This activity, however, was not well separated from cytotoxicity, IC50's = 10-100 microM. The corresponding unsubstituted, the 5,6-dimethyl, and the 5,6-difluoro ribonucleosides (19, 20, and 2, respectively), were inactive against both viruses. Similar to the previously reported 2,5,6-trichloro analog (TCRB), the 5,6-dibromo ribonucleoside 3 was active against HCMV (IC50 approximately 4 microM) but more cytotoxic than TCRB. The 5,6-diiodo analog 4 also was active (IC50 approximately 2 microM) but more cytotoxic (IC50 = 10-20 microM) than either 3 or TCRB. The cyclonucleosides were inactive against both viruses and not cytotoxic, or slightly active with corresponding cytotoxicity. The order of activity against HCMV of the dihalobenzimidazole ribonucleosides was I approximately equal to Br approximately equal to CI > > F > H = CH3. The order of cytotoxicity among the most active compounds, however, was I > Br > Cl, thereby establishing that TCRB had the best antiviral properties.

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Section: Resultsmentioning

confidence: 99%

Section: (6)-amino-2-chloro-6(5)-nitrobenzimidazole (12)mentioning

confidence: 99%

Section: 6-difluoro-1-r-d-ribofuranosylbenzimidazole 22′-o-cyclonucle...mentioning

confidence: 99%

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Design, Synthesis, and Antiviral Evaluation of 2-Chloro-5,6-dihalo-1-β-d-ribofuranosylbenzimidazoles as Potential Agents for Human Cytomegalovirus Infections

1997

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“…In our second approach, 2-chloro-5(6)-nitrobenzimidazole − ( 3 ) was similarly ribosylated to give the desired β nucleosides 4a , b in 71% yield as a mixture of positional isomers {2-chloro-5-nitro-1-(2,3,5-tri- O -acetyl-β- d -ribofuranosyl)benzimidazole ( 4a ) and 2-chloro-6-nitro-1-(2,3,5-tri- O -acetyl-β- d -ribofuranosyl)benzimidazole ( 4b )}. The positional isomers 4a , b , which, like 2a , b , could not be separated via silica chromatography and gave only one pure isomer in low yield upon repeated recrystallization, was directly converted to the corresponding amino derivatives 5 and 6 by hydrogenation over Raney nickel.…”

Section: Chemistrymentioning

confidence: 99%

Synthesis and Antiviral Evaluation of Certain Disubstituted Benzimidazole Ribonucleosides

et al. 1996

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Ribosylation of 2-chloro-5(6)-nitrobenzimidazole (3) gave 2-chloro-5-nitro-1-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)benzimidazol e (4a) and 2-chloro-6-nitro-1-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)benzimidazol e (4b) as a mixture of positional isomers. Subsequent hydrogenation of this mixture over Raney Nickel afforded the corresponding 5-amino and 6-amino derivatives 5 and 6. At this stage the products were readily resolved via silica column chromatography into pure isomeric forms, and the pure isomers 5 and 6 were diazotized with tert-butyl nitrite and cupric chloride to furnish the isomerically pure 5-chloro derivative 2a and 6-chloro derivative 2b. Deprotection of 5, 6, 2a, and 2b with methanolic ammonia yielded the free nucleosides 5-amino-2-chloro-1-(beta-D-ribofuranosyl)benzimidazole (7), 6-amino-2-chloro-1-(beta-D-ribofuranosyl)-benzimidazole (8), 2,5-dichloro-1-(beta-D-ribofuranosyl)benzimidazole (9), and 2,6-dichloro-1-(beta-D-ribofuranosyl)benzimidazole (10), respectively. Treatment of 10 with thiourea afforded 6-chloro-1-(beta-D-ribofuranosyl)benzimidazole-2-thione (14). Alkylation of 14 with methyl iodide and benzyl bromide gave good yields of the corresponding 2-methylthio (12) and the 2-benzylthio (13) analogs. The synthesis of 6-chloro-2-methoxy-1-(beta-D-ribofuranosyl)benzimidazole (11) was accomplished by the treatment of 2b with sodium methoxide in methanol. A difference NOE spectroscopic experiment was conducted to allow unequivocal assignment of regiochemistry to the positional isomers 5 and 6. Evaluation of compounds for activity against human cytomegalovirus (HCMV) and herpes simplex virus type 1 revealed that the heterocycle 3 was active against both viruses but also was cytotoxic. Only the dichloro compounds 9 and 10 were weakly active against HCMV and noncytotoxic in their antiviral dose range. These data further substantiate the conclusion that activity against HCMV at noncytotoxic concentrations by benzimidazole ribonucleosides requires a halogen not only at the 2-position, but also more than one halogen on the benzene moiety.

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“…In order to expand the structural variety of this class of compounds, we have studied the functionalization of previously reported 11 It was expected that incorporation of an electrophilic moiety at the ortho position with respect to the electron-withdrawing substituent would be observed for azaheterocycles of this type, in a similar manner to the nitration of 5(6)-nitrobenzimidazoles (Scheme 2). [12][13][14][15][16][17][18][19] Introduction of the nitrogroup was initially examined using pyrido[1,2-a]benzimidazole 1a and potassium nitrate in H 2 SO 4 ( Table 1, entry 1). It was observed that a single dinitrosubstituted product formed within 1 hour at 20 °C in 91 % yield.…”

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confidence: 99%