Antiviral Activity of a bis-Benzimidazole Against Experimental Rhinovirus Infections in Chimpanzees

Shipkowitz, N. L.; Bower, R. R.; Schleicher, J. B.; Aquino, Francisco José Tôrres de; Appell, R. N.; Roderick, William R.

doi:10.1128/am.23.1.117-122.1972

Cited by 17 publications

(2 citation statements)

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“…[18][19][20] As a part of our continuous efforts to develop anti-virus agents, [21][22][23][24] herein, a series of novel small molecules with a thiophene-carboxamide core, different from the classical core structures of anti-EV71 compounds (as shown in Fig. 1), [18][19][20]25,26 were developed and assayed for antiviral activity against EV71. Preliminary screenings showed that lead compound 5a has considerable potency relative to the drug compound enviroxime 4 and a broad spectrum of activity against both human rhinoviruses and enteroviruses, [27][28][29][30][31] which were tested at a low micromolar range (Fig.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of N-benzyl-N-phenylthiophene-2-carboxamide analogues as a novel class of enterovirus 71 inhibitors

et al. 2015

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A series of novel human enterovirus 71 inhibitors, N-benzyl-N-phenylthiophene-2-carboxamide analogues were 10 synthesized and their antiviral activities were evaluated in vitro. Most derivatives of this structure against EV71 with a low micromolar range in the RD (Rhabdomyosarcoma) cell lines. The most potent compound 5a, N-(4-bromobenzyl)-N-(4-fluorophenyl)thiophene-2-carboxamide, showed low 15 micromolar activity against EV71 (EC 50 = 1.42 µM) compared to the reference anti-EV71 drug Enviroxime (EC 50 = 0.15 µM). Preliminary SAR studies revealed that thiophene-2carboxamide core is crucial for maintaining antiviral activity, and N-substituent phenyl groups largely influenced anti-20 EV71 efficacy of this new class of potent antiviral agents.

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Section: Introductionmentioning

confidence: 99%

Synthesis of N-benzyl-N-phenylthiophene-2-carboxamide analogues as a novel class of enterovirus 71 inhibitors

et al. 2015

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“…The benzimidazoles − are a unique, potent, and broad-spectrum class of antirhino/enteroviral agents discovered over 25 years ago through routine screening of Lilly's research file compounds against rhino- and polioviruses. − In the early 1980s, two candidates from this series, Enviroxime and Enviradene (Chart ), were evaluated in the clinic. Enviroxime ( 1 ) possesses significant antiviral activity against human rhinovirus 14 (HRV-14) (IC 50 = 0.05 μg/mL) as well as a broad spectrum of activity against both rhino- and enteroviruses. − However, when Enviroxime was dosed orally in humans, it showed very low blood levels and caused an emetic response similar to that observed earlier in toxicology studies in dogs.…”

Section: Introductionmentioning

confidence: 99%

Antirhino/Enteroviral Vinylacetylene Benzimidazoles: A Study of Their Activity and Oral Plasma Levels in Mice

et al. 1997

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In an effort to find an orally bioavailable antiviral for the treatment of rhino/enteroviral infections, a series of vinylacetylene benzimidazoles (11a-o, 12, and 18a) was made. Initial studies of this class of antivirals showed that fluorine substitution on the left-hand phenyl ring in combination with the vinylacetylene moiety gave the requisite mix of physical properties to achieve good in vitro antiviral activity as well as respectable oral bioavailability in rhesus monkeys. To ascertain the generality of this finding and to broaden the scope of the structure-activity relationship (SAR), the present study concentrated on fluoro substitution of this class of molecules. The initial antiviral activity for each analogue was measured using human rhinovirus 14 (HRV-14). This served as an indicator of general antiviral activity for SAR purposes. Subsequently, the spectrum of antirhino/enteroviral activity of the more interesting analogues was evaluated through testing against a panel of seven additional rhino/enteroviruses. Broad-spectrum activity was present and consistent for all analogues tested, and it tracked closely with the antiviral activity observed against HRV-14. A simple screening protocol for oral bioavailability was established whereby compounds were administered orally to mice and plasma levels were measured. This procedure facilitated the evaluation of numerous analogues in a rapid manner. The Cmax was used as a measure of oral bioavailability to allow relative ranking of compounds. In general, fluorine substitution directly on the left-hand aromatic ring does give good oral blood levels. However, fluorine incorporation at other positions in the molecule was not as effective at maintaining either the activity or the oral plasma levels. The constructive combination of activity and oral plasma levels was maximized in three derivatives: 11a,e,g.

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Antiviral Agents

Revankar¹,

Robins²

2000

Kirk-Othmer Encyclopedia of Chemical Technology

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Viral infections are among the greatest causes of human morbidity, and it is estimated that in developed countries more than 60% of all the episodes of human illness result from viral infections. High virus infection rates also occur among pets, livestock, and plants. The high morbidity and the resulting economic loss caused by these infections have generated tremendous efforts in recent years to develop antiviral agents. Since viruses propagate only within living cells, the development of antiviral drugs which would disrupt the viral replication without affecting the metabolism of the host cell was initially believed to be difficult, if not impossible. However, dramatic progress in viral molecular biology has now made it possible to identify enzymatic processes which are unique to virus‐infected cells. As a consequence, it is becoming feasible to design chemical compounds which identify infected cells, block a specific step in viral replication, and leave uninfected cells unharmed. The majority of antiviral drugs which are under clinical development today generally interrupt viral nucleic acid synthesis. These compounds possess considerable selectivity against virus‐induced enzymes. This article discusses agents exhibiting significant antiviral activity against viral infections in animal model systems. One of the simplest molecules found to inhibit the replication of DNA viruses in animals is phosphonoformic acid (PFA), CH 3 O 5 P. PFA has undergone clinical evaluation in humans for the treatment of recurrent genital herpes, hepatitis B viral infection, and acquired immunodeficiency syndrome (AIDS), as well as cytomegalovirus (CMV) infection of bone marrow and renal transplant patients. Levamisole (6‐phenyl‐2,3,5,6‐tetrahydroimidazol[2,1‐ b ]thiazole), C 11 H 12 N 2 S, was found to be effective against herpes virus infections in humans. Several pyrimidine bases have been found to inhibit herpes virus‐induced keratitis in rabbits, eg, 2‐amino‐4,6‐dichloropyrimidine, C 4 H 3 Cl 2 N 3 , and 1‐allyl‐6‐chloro‐3,5‐diethyluracil, C 11 H 15 ClN 2 O 2 . The most successful clinical antiviral agents belong to the nucleoside category. Nucleoside analogues with potent antiviral activity have been known since idoxuridine and trifluridine were shown to be efficacious against herpes keratitis more than 30 years ago. However, the therapeutic usefulness of these early nucleosides was limited because of mutagenic, teratogenic, carcinogenic, cytostatic, or cytotoxic side effects. Recently the specificity of antiviral action of this class of compounds has been significantly improved; potent and highly selective nucleoside antiviral agents have now been developed. These include cytosine derivatives, purine nucleoside derivatives, adenine derivatives, and acyclic purine nucleosides. Among agents active against RNA viruses, 1,2‐bis(5‐methoxy‐2‐benzimidazol‐2‐yl)‐1,2‐ethanediol, C 18 H 18 N 4 O 4 , was found to be active against an experimentally induced rhino virus infection in chimpanzees. However, the in vivo antiviral efficacy was accompanied by significant toxicity. Amantadine hydrochloride (1‐adamantanamine hydrochloride), \documentclass{article}\usepackage{amssymb}\pagestyle{empty}\begin{document}${{\rm{C}}{\rm{H}}{\rm{N}}{\rm{{\cdot{}}}}{\rm{HCl}}1710}$\end{document} , is a narrow‐spectrum agent active only against influenza A virus. It became the first antiviral drug available for systemic use in the United States when it was approved by the FDA in 1966 for use against Asian influenza. A structurally related drug, rimantadine hydrochloride, (α‐methyl‐1‐adamantanemethylamine hydrochloride), \documentclass{article}\usepackage{amssymb}\pagestyle{empty}\begin{document}${{\rm{C}}{\rm{H}}{\rm{N}}{\rm{{\cdot{}}}}{\rm{HCl}}2112}$\end{document} , is widely used in Russia to treat influenza A virus. Lipophilic β‐diketones have exhibited significant in vivo activity against a number of RNA viruses, and adenosine and guanosine analogues have been found to be active against both RNA and DNA viruses. One of the broad‐spectrum antiviral agents that emerged from ICN Pharmaceuticals is an azole ribonucleoside, 1‐β‐ D ‐ribofuranosyl‐1,2,4‐triazole‐3‐carboxamide, designated as ribavirin, C 8 H 12 N 4 O 5 . Ribavirin has been studied in more animals and against more viruses than any other antiviral agent known today. It is active in cell culture against approximately 85% of all viruses studied. Viral strains susceptible to ribavirin have not been found to develop a resistance to the drug. The resistance against ribavirin is less likely because the drug exhibits multiple sites of antiviral action. Retroviruses as a class are often found to be responsible for persistent viral infections. Retroviruses are unique RNA viruses characterized by the transcription of their single‐stranded RNA into the double‐stranded DNA of the host cell using the viral enzyme reverse transcriptase. AIDS is an example of such a persistent and latent human viral infection. Following the identification of a retrovirus, HIV, as the etiological agent of AIDS, an intense effort has been made to identify drugs for the treatment or prevention of this debilitating, lethal disease. Several 2′,3′‐dideoxyribonucleosides of purine and pyrimidine were discovered to be potent inhibitors of HIV replication in vitro . Considerable data has also accumulated on in vitro antiHIV testing of acyclic and carbocyclic nucleoside analogues. 3′‐Azido‐3′‐deoxythymidine (retrovir, zidovudine, AZT), C 10 H 13 N 5 O 4 , 2,′3′‐dideoxycytidine (DDC), C 9 H 13 N 3 O 3 , and 2′,3′‐dideoxyinosine (DDI), C 10 H 12 N 4 O 3 , have become widely available for the treatment of AIDS and approved by the FDA for treatment of advanced AIDS cases.

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Antiviral Activity of a bis-Benzimidazole Against Experimental Rhinovirus Infections in Chimpanzees

Cited by 17 publications

References 4 publications

Synthesis of N-benzyl-N-phenylthiophene-2-carboxamide analogues as a novel class of enterovirus 71 inhibitors

Synthesis of N-benzyl-N-phenylthiophene-2-carboxamide analogues as a novel class of enterovirus 71 inhibitors

Antirhino/Enteroviral Vinylacetylene Benzimidazoles: A Study of Their Activity and Oral Plasma Levels in Mice

Antiviral Agents

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