Synthesis and Biological Properties of Certain 5,6-Dichlorobenzimidazole Ribosides

Kissman, Henry M.; Child, Ralph G.; Weiss, Martin J.

doi:10.1021/ja01562a041

Cited by 15 publications

(8 citation statements)

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“…Reaction of the mercury salt of 5-amino-4-nitropyrazole and tribenzoylribfuranose chloride20 in heated toluene gave exclusively the 3-amino-4-nitropyrazole nucleoside.…”

Section: Resultsmentioning

confidence: 99%

Interrogating the mechanism of a tight binding inhibitor of AIR carboxylase

Firestine

Youn

et al. 2009

Bioorganic & Medicinal Chemistry

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The enzyme aminoimidazole ribonucleotide (AIR) carboxylase catalyzes the synthesis of the purine intermediate, 4-carboxy-5-aminoimidazole ribonucleotide (CAIR). Previously, we have shown that the compound 4-nitro-5-aminoimidazole ribonucleotide (NAIR) is a slow, tight binding inhibitor of the enzyme with a K i of 0.34 nM. The structural attributes and the slow, tight binding characteristics of NAIR implicated this compound as a transition state or reactive intermediate analog. However, it is unclear what molecular features of NAIR contribute to the mimetic properties for either of the two proposed mechanisms of AIR carboxylase. In order to gain additional information regarding the mechanism for the potent inhibition of AIR carboxylase by NAIR, a series of heterocyclic analogs were prepared and evaluated. We find that all compounds are weaker inhibitors than NAIR and that CAIR analogs are not alternative substrates for the enzyme. Surprisingly, rather subtle changes in the structure of NAIR can lead to profound changes in binding affinity. Computational investigations of enzyme intermediates and these inhibitors reveal that NAIR displays an electrostatic potential surface similar to a proposed reaction intermediate. The result indicates that AIR carboxylase is likely sensitive to the electrostatic surface of reaction intermediates and thus compounds which mimic these surfaces should possess tight binding characteristics. Given the evolutionary relationship between AIR carboxylase and N 5 -CAIR mutase, we believe that this concept extends to the mutase enzyme as well. The implications of this hypothesis for the design of selective inhibitors of the N 5 -CAIR mutase are discussed.

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“…Reaction of the mercury salt of 5-amino-4-nitropyrazole and tribenzoylribfuranose chloride20 in heated toluene gave exclusively the 3-amino-4-nitropyrazole nucleoside.…”

Section: Resultsmentioning

confidence: 99%

Interrogating the mechanism of a tight binding inhibitor of AIR carboxylase

Firestine

Youn

et al. 2009

Bioorganic & Medicinal Chemistry

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“…Furthermore, Raney nickel mediated dethiation of 5 furnished a compound with the same properties as those reported for DRB. 19 Previous reports of l-/?-D-ribofuranosylbenzimidazole nucleosides29-31 indicate that the Jy.%' coupling constants tend to be >5 Hz for such compounds and therefore cannot be used to establish anomeric configuration. We found that all nucleosides (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23) prepared in this study possessed a Jy.% >5 Hz.…”

Section: Introductionmentioning

confidence: 99%

“…19 Previous reports of l-/?-D-ribofuranosylbenzimidazole nucleosides29-31 indicate that the Jy.%' coupling constants tend to be >5 Hz for such compounds and therefore cannot be used to establish anomeric configuration. We found that all nucleosides (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23) prepared in this study possessed a Jy.% >5 Hz. However, the dethiation of 5 to give DRB (with a Jy.y of 6.3 Hz) established the /3-anomeric configuration for all nucleosides (4-23).…”

Section: Introductionmentioning

confidence: 99%

“…However, the dethiation of 5 to give DRB (with a Jy.y of 6.3 Hz) established the /3-anomeric configuration for all nucleosides (4-23). Compounds [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] were obtained by the treatment of 4 with a base followed by the addition of an appropriate alkenyl, alkynyl, or benzyl halide (Schemes 1 and 2). The 2-methylsulfonyl compound (6) was obtained from the corresponding 2-methylthio compound (5) by oxidation with the magnesium hexahydrate salt of monoperoxyphthalic acid (MMPP) in acetonitrile at 0 °C.…”

Section: Introductionmentioning

confidence: 99%

“…Using this approach, we synthesized and evaluated several new analogs. Although most of the compounds (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23) demonstrated some activity against HCMV and HSV-1, there was little or no separation from cytotoxicity in either HFF or KB cells (Table 2). Thus the parent compound, 7, was as or more active against HCMV and less cytotoxic than the substituted analogs.…”

Section: Introductionmentioning

confidence: 99%

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Benzimidazole Ribonucleosides: Design, Synthesis, and Antiviral Activity of Certain 2-(Alkylthio)- and 2-(Benzylthio)-5,6-dichloro-1-(.beta.-D-ribofuranosyl)benzimidazoles

Devivar

Kawashima²,

Revankar³

et al. 1994

J. Med. Chem.

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Several 2-alkylthio- and 2-benzylthio derivatives of 5,6-dichloro-1-(beta-D-ribofuranosyl)benzimidazole (DRB) have been designed and synthesized from 5,6-dichloro-1-(beta-D-ribofuranosyl)-benzimidazole-2-thione. All compounds were evaluated for activity against human cytomegalovirus (HCMV) and/or herpes simplex virus type-1 (HSV-1). Three different cytotoxicity assays were used to determine if the compounds were toxic to uninfected cells. Most of the 2-alkylthio compounds were either inactive against HCMV and HSV-1 or were active only at concentrations at or near those which produced toxicity in uninfected cells. The best separation between activity against HCMV and cytotoxicity was observed with the 2-benzylthio analog 7. This prompted us to synthesize the substituted 2-benzylthio analogs 11-23 using a Topliss Tree approach. None of these compounds were more active than compound 7; most of the analogs were weakly active against both HCMV and HSV-1, but the activity was not separated from cytotoxicity. On the basis of both antiviral and cytotoxicity data, compound 7 was the best compound in the series. It was more active against HCMV than DRB (the 2-unsubstituted analog), acyclovir, and foscarnet, but it was less active than ganciclovir.

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