RESUMEN
BACKGROUND: Adamantane-based compounds have been identified to interfere with the ion-channel activity of viroporins and thereby inhibit viral infection. To better understand the difference in the inhibition mechanism of viroporins, we synthesized symmetric dimeric adamantane analogs of various alkyl-spacer lengths. METHODS: Symmetric dimeric adamantane derivatives were synthesized where two amantadine or rimantadine molecules were linked by various alkyl-spacers. The inhibitory activity of the compounds was studied on two viroporins: the influenza virus M2 protein, expressed in Xenopus oocytes, using the two-electrode voltage-clamp technique, and the hepatitis C virus (HCV) p7 channels for five different genotypes (1a, 1b, 2a, 3a, and 4a) expressed in HEK293 cells using whole-cell patch-clamp recording techniques. RESULTS: Upon testing on M2 protein, dimeric compounds showed significantly lower inhibitory activity relative to the monomeric amantadine. The lack of channel blockage of the dimeric amantadine and rimantadine analogs against M2 wild type and M2-S31N mutant was consistent with previously proposed drug-binding mechanisms and further confirmed that the pore-binding model is the pharmacologically relevant drug-binding model. On the other hand, these dimers showed similar potency to their respective monomeric analogs when tested on p7 protein in HCV genotypes 1a, 1b, and 4a while being 700-fold and 150-fold more potent than amantadine in genotypes 2a and 3a, respectively. An amino group appears to be important for inhibiting the ion-channel activity of p7 protein in genotype 2a, while its importance was minimal in all other genotypes. CONCLUSION: Symmetric dimeric adamantanes can be considered a prospective class of p7 inhibitors that are able to address the differences in adamantane sensitivity among the various genotypes of HCV.
Asunto(s)
Adamantano/farmacología , Amantadina/farmacología , Antivirales/farmacología , Rimantadina/farmacología , Proteínas de la Matriz Viral/antagonistas & inhibidores , Proteínas Virales/antagonistas & inhibidores , Adamantano/síntesis química , Adamantano/química , Amantadina/síntesis química , Amantadina/química , Antivirales/síntesis química , Antivirales/química , Células Cultivadas , Diseño de Fármacos , Células HEK293 , Humanos , Modelos Moleculares , Estructura Molecular , Rimantadina/síntesis química , Rimantadina/química , Proteínas de la Matriz Viral/metabolismo , Proteínas Virales/metabolismoRESUMEN
The amino acid and peptide derivatives of 1-adamantane carboxylic acid and rimantadine (18 compounds) have been first synthesized and investigated for their activity against influenza A virus (H1N1, H1N1v). In a series of obtained adamantine derivatives, some compounds have been found to be able to inhibit rimantadine-resistant influenza A virus strains. Thus, the antiviral properties of rimantadine can be restored.
Asunto(s)
Adamantano/análogos & derivados , Antivirales/farmacología , Farmacorresistencia Viral/efectos de los fármacos , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , Gripe Humana/tratamiento farmacológico , Rimantadina/farmacología , Adamantano/síntesis química , Adamantano/farmacología , Adamantano/uso terapéutico , Amantadina/análogos & derivados , Amantadina/síntesis química , Amantadina/farmacología , Amantadina/uso terapéutico , Antivirales/síntesis química , Antivirales/uso terapéutico , Humanos , Rimantadina/análogos & derivados , Rimantadina/síntesis química , Rimantadina/uso terapéuticoRESUMEN
Influenza is a major threat to millions of people worldwide. Vaccines and antiviral agents are two main options available to reduce the impact of the influenza virus, while anti-influenza agents are the most effective means to prevent the transmission of the highly contagious virus and to treat the epidemics of disease. At present, four anti-influenza agents have been approved by the FDA for the treatment of influenza, including two M2 protein ion channel inhibitors-amantadine and rimantadine and two neuraminidase inhibitors-zanamivir and oseltamivir. Arbidol hydrochloride, launched in Russia, is a potent inhibitor of influenza virus, too. Neuraminidase inhibitors could be classified generally by structure into six different kinds: sialic acid derivatives, benzoic acid derivatives, cyclohexene derivatives, cyclopentane derivatives, pyrrolidine derivatives and natural products. In this paper, recent progress in the research of the action mechanisms and structure-activity relationships of these anti-influenza virus agents were reviewed.
Asunto(s)
Antivirales , Neuraminidasa/antagonistas & inhibidores , Orthomyxoviridae/efectos de los fármacos , Proteínas de la Matriz Viral/antagonistas & inhibidores , Ácidos Carbocíclicos , Amantadina/síntesis química , Amantadina/química , Amantadina/farmacología , Amantadina/uso terapéutico , Antivirales/síntesis química , Antivirales/química , Antivirales/farmacología , Antivirales/uso terapéutico , Ciclopentanos/síntesis química , Ciclopentanos/química , Ciclopentanos/farmacología , Ciclopentanos/uso terapéutico , Guanidinas/síntesis química , Guanidinas/química , Guanidinas/farmacología , Guanidinas/uso terapéutico , Humanos , Indoles/síntesis química , Indoles/química , Indoles/farmacología , Indoles/uso terapéutico , Gripe Humana/tratamiento farmacológico , Neuraminidasa/síntesis química , Neuraminidasa/química , Neuraminidasa/farmacología , Neuraminidasa/uso terapéutico , Oseltamivir/síntesis química , Oseltamivir/química , Oseltamivir/farmacología , Oseltamivir/uso terapéutico , Pirrolidinas/síntesis química , Pirrolidinas/química , Pirrolidinas/farmacología , Pirrolidinas/uso terapéutico , Rimantadina/síntesis química , Rimantadina/química , Rimantadina/farmacología , Rimantadina/uso terapéutico , Relación Estructura-Actividad , Proteínas de la Matriz Viral/síntesis química , Proteínas de la Matriz Viral/química , Proteínas de la Matriz Viral/farmacología , Proteínas de la Matriz Viral/uso terapéutico , Zanamivir/síntesis química , Zanamivir/química , Zanamivir/farmacología , Zanamivir/uso terapéuticoRESUMEN
1-2 Annulated adamantane piperidines 4, 6, 16, 17, 19, 23 and 25 were synthesized and evaluated for anti-influenza A virus activity. The stereoelectronic requirements for optimal antiviral potency were investigated. Piperidine 23 proved to be the most active of the compounds tested against influenza A virus, being 3.5-fold more active than amantadine, equipotent to rimantadine and 15-fold more potent than ribavirin. It is noteworthy that piperidine 23 displayed one of the highest selectivity indexes (SI>732) among aminoadamantanes or other cage structure amines tested till now.
Asunto(s)
Adamantano/síntesis química , Adamantano/farmacología , Subtipo H3N2 del Virus de la Influenza A/efectos de los fármacos , Piperidinas/química , Piperidinas/farmacología , Adamantano/química , Animales , Antivirales/síntesis química , Antivirales/química , Antivirales/farmacología , Perros , Humanos , Espectroscopía de Resonancia Magnética , Estructura Molecular , Piperidinas/síntesis química , Rimantadina/síntesis química , Rimantadina/farmacología , Relación Estructura-ActividadRESUMEN
Adamantanopyrrolidines 8, 9 and 10, adamantanopyrrolidines 16 and 18, adamantanoxazolone 20, adamantanopyrazolone 23, adamantanopyrazolothione 24 and adamantanocyclopentanamine 32 were synthesized and tested for anti-influenza A virus and trypanocidal activity. The stereoelectronic requirements for optimal antiviral and trypanocidal potency were investigated. Pyrrolidine 16 proved to be the most active of the compounds tested against influenza A virus, being 4-fold more active than amantadine, equipotent to rimantadine and 19-fold more potent than ribavirin. Oxazolone 20 showed significant trypanocidal activity against bloodstream forms of the African trypanosome, Trypanosoma brucei, being approximately 3 times more potent than rimantadine and almost 50-fold more active than amantadine.
Asunto(s)
Amantadina/síntesis química , Antivirales/síntesis química , Diseño de Fármacos , Rimantadina/síntesis química , Tripanocidas/síntesis química , Amantadina/química , Amantadina/uso terapéutico , Animales , Antivirales/química , Antivirales/uso terapéutico , Subtipo H3N2 del Virus de la Influenza A/patogenicidad , Infecciones por Orthomyxoviridae/tratamiento farmacológico , Ribavirina/uso terapéutico , Rimantadina/química , Rimantadina/uso terapéutico , Porcinos , Tripanocidas/química , Tripanocidas/farmacología , Trypanosoma brucei brucei/efectos de los fármacos , Tripanosomiasis Africana/tratamiento farmacológico , Proteínas de la Matriz Viral/metabolismoRESUMEN
We examined whether the incorporation of a second amino group into the 1-aminoethyl pharmacophore of rimantadine 2 and into the piperidine pharmacophore of the heterocyclic rimantadine 4 was compatible with anti-influenza virus A activity. The new synthetic molecules are capable of forming two hydrogen bonds within the receptor. We identified molecules 8 and 16, bearing the adamantyl and 1,2-diaminoethyl groups, which are equipotent to rimantadine 2 bearing the adamantyl and 1-aminoethyl pharmacophore groups. Interestingly, diamino compound 16 is a 4-fold more potent inhibitor than its parent monoamino heterocyclic rimantadine 4 propably because of additional hydrogen bonding interactions with the M2 protein receptor.
Asunto(s)
Antivirales/síntesis química , Antivirales/farmacología , Virus de la Influenza A/efectos de los fármacos , Rimantadina/análogos & derivados , Rimantadina/síntesis química , Aminación , Animales , Línea Celular , Perros , Indicadores y Reactivos , Subtipo H3N2 del Virus de la Influenza A/efectos de los fármacos , Espectroscopía de Resonancia Magnética , Metilación , Rimantadina/farmacología , Relación Estructura-Actividad , Replicación ViralRESUMEN
2-(1-Adamantyl)pyrrolidines 6, 7, 2-(1-adamantyl)piperidines 10, 12a-c, 15a,b and 2-(1-adamantyl)hexahydroazepines 19, 21, 22 were synthesized and tested for their antiviral activity against influenza A, B viruses and the human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2). The synthetic procedure followed for the preparation of the parent piperidine 10 represents a general method for the synthesis of 2-alkyl- or cycloalkyl-substituted piperidine alkaloids. Parent aminoadamantanes 6, 10 and 19 contain the 1-aminoethyl pharmacophore group of rimantadine drug 2, extended into a saturated nitrogen heterocycle: pyrrolidine, piperidine and hexahydroazepine, respectively. The ring size effect in anti-influenza A activity was investigated. Rimantadine analogues 6 and 10 were, respectively, 6- and 4-fold more active than the drug Rimantadine 2, whereas the hexahydroazepine derivative 19 was inactive. Thus, enlargement from a 5-(pyrrolidine)- or 6-(piperidine)- to a 7-(hexahydroazepine)- membered heterocyclic ring dramatically reduced the anti-influenza virus A activity. Substitution of piperidine 10 with a dialkyaminoethyl group led to the active compounds 15a and 15b: compound 15a was active against influenza A virus whereas both 15a and 15b were active against HIV-1.
Asunto(s)
Antivirales/farmacología , Rimantadina/análogos & derivados , Antivirales/síntesis química , Antivirales/toxicidad , Línea Celular , VIH-1/efectos de los fármacos , VIH-2/efectos de los fármacos , Humanos , Virus de la Influenza A/efectos de los fármacos , Virus de la Influenza B/efectos de los fármacos , Estructura Molecular , Rimantadina/síntesis química , Rimantadina/farmacología , Rimantadina/toxicidad , Relación Estructura-ActividadRESUMEN
Chemical synthesis of 3-substituted analogues of remantadine is described. Derivatives IIIb and IIIc when compared with remantadine had not only potent activity against ethalon herpes simplex type 1 virus strain but also were active against herpes virus resistant to aciclovir. Compound IIIc demonstrated virulecidal effect. Combination of IIIc + aciclovir had additive effect against ethalon herpes simplex type 1 virus strain. Investigated 3-substituted analogues demonstrated low activity in the model system of influenzae virus. No antiviral activity was demonstrated in the model system of Syndbys virus (though compounds were evaluated in subtoxic concentrations).
Asunto(s)
Antivirales/síntesis química , Antivirales/farmacología , Rimantadina/síntesis química , Rimantadina/farmacología , Simplexvirus/efectos de los fármacos , Aciclovir/administración & dosificación , Aciclovir/síntesis química , Aciclovir/farmacología , Animales , Antivirales/administración & dosificación , Chlorocebus aethiops , Rimantadina/administración & dosificación , Células VeroRESUMEN
The hydroxy metabolites of rimantadine (3-5) were synthesized and compared to amantadine (1) and rimantadine (2) for their ability to inhibit the replication of influenza viruses in vitro. All three metabolites were inhibitory to wild-type influenza A viruses (H3N2 and H1N1). In particular, 2-hydroxyrimantadine (3) showed similar activity to amantadine, but the 3- and 4-hydroxy metabolites (4 and 5, respectively), both of which are found in rimantadine-treated patients, showed only modest inhibitory activity. A rimantadine-resistant isolate of influenza A virus exhibited cross-resistance to amantadine and to each of the metabolites 3-5. None of the compounds were effective against influenza B virus.