Effect of N-methylisatin-β-4′:4′-diethylthiosemicarbazone on intracellular Moloney leukemia virus constituents

Ronen, Denise; Nir, E.; Teitz, Yael

doi:10.1016/0166-3542(85)90029-4

Cited by 15 publications

(11 citation statements)

References 13 publications

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“…Mais tarde foi demonstrado que tiossemicarbazonas derivadas de 2-acetilpiridina, 2-acetilquinolina e 1-acetilquinolina eram ativas contra HSV in vitro e em um modelo in vivo de herpes cutâneo 68 . Além disso, foi mostrada a atividade de derivados dialquil-substituídos da N-metilisatina tiossemicarbazona contra o vírus da leucemia Moloney, um membro da família dos retrovírus 69 . Recentemente, um estudo de relações estrutura-atividade de uma série de tiossemicarbazonas α(N)-heterocíclicas estabeleceu relações entre a atividade e alguns parâmetros físico-químicos 70 .…”

Section: Tiossemicarbazonas E Seus Complexos Com Outros Cátions Metálunclassified

Semicarbazonas e tiossemicarbazonas: o amplo perfil farmacológico e usos clínicos

Beraldo¹

2004

Quím. Nova

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Recebido em 31/7/03; aceito em 24/9/03 SEMICARBAZONES AND THIOSEMICARBAZONES: THEIR WIDE PHARMACOLOGICAL PROFILE AND CLINICAL APPLICATIONS. This article shows that thiosemicarbazones, semicarbazones and their metal complexes can exhibit target selectivity along with a wide pharmacological profile. Complexes of thiosemicarbazones with cytotoxic or antitumoral activity are presented, some of which show activity against cisplatinum-resistant cells. The inhibition mechanism of the enzyme ribonucleoside diphosphate reductase (RDR), involved in DNA syntheses, by α(N)-heterocyclic thiosemicarbazones is discussed. The encouraging results of clinical trials with the RDR inhibitor 3-aminopyridine-2-carboxaldehyde thiosemicarbazone ("Triapine") against rapidly growing tumors are outlined. Examples are also given of thiosemicarbazones with antiviral and antimicrobial activity. The possible applications of semicarbazones as anticonvulsants with low toxicity and good therapeutic index are presented. . Ehrlich foi o fundador da quimioterapia e introduziu as primeiras idéias sobre relações estrutura-atividade e o conceito de índice terapêutico. Fez ainda uso de complexos metálicos, em especial os de arsênio, na preparação de drogas para o tratamento da sífilis 2 . Werner é considerado o pai da Química de Coordenação pelo desenvolvimento de sua teoria para explicar a estrutura e a ligação química nos complexos metálicos.Apesar da grande importância dos trabalhos desses e de outros pesquisadores, a Química Medicinal dedicou-se, durante muitos anos, principalmente ao estudo de compostos orgânicos e produtos naturais. A investigação a respeito do uso de complexos metálicos como fármacos teve início, de modo sistemático, apenas após a descoberta feita pelo físico Barnett Rosemberg, da atividade antitumoral do cis(diaminodicloro)platina(II), o "cisplatina" ou cis-ddp, em 1965 3 . Desde então, uma imensa variedade de complexos metálicos foi e tem sido investigada quanto às suas propriedades terapêuticas. É interessante observar que o primeiro número da revista Metal-Based Drugs apareceu em 1994.Tiossemicarbazonas e semicarbazonas (Figura 1) apresentam um amplo perfil farmacológico e constituem uma importante classe de compostos cujas propriedades têm sido extensivamente estudadas na Química Medicinal e, particularmente, na Química Medicinal Inorgânica, em razão de sua capacidade quelante e do papel da coordenação no seu mecanismo bioquímico de ação. Apesar da ampla versatilidade farmacológica desses compostos como uma classe, especificidades estruturais podem levar à manifestação de atividades específicas. Para os complexos metálicos, em alguns casos é possí-vel modular a atividade através do desenho do ligante ou através da escolha do metal, como veremos adiante.De modo geral pode-se dizer que tiossemicarbazonas e semicarbazonas agem, seja como inibidores de enzimas, através da complexação de metais endógenos ou através de reações de redox, seja através de interações com o ADN e da inibição da síntese do ADN. Além disso, alguns compl...

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Section: Tiossemicarbazonas E Seus Complexos Com Outros Cátions Metálunclassified

Semicarbazonas e tiossemicarbazonas: o amplo perfil farmacológico e usos clínicos

Beraldo¹

2004

Quím. Nova

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“…We were the first to show that M-IBDET inhibits the production of M-MuLV Sherman et al, 1980), a member of the retrovirus family. It was shown that M-IBDET specifically inhibits M-MuLV structural protein synthesis by blocking the translation process of M-MuLV mRNA (Ronen and Teitz, 1984;Ronen et al, 1985Ronen et al, , 1987 In an attempt to understand the inhibition of FIV by the TSCD, we examined the effect of A-IBDAT on the synthesis of the FIV gag gene encoding p24 protein. Our pulse-labelling experiments showed that the drug is involved in inhibition of this protein synthesis, and the degree of inhibition is proportional to the druq concentration.…”

Section: Discussionmentioning

confidence: 99%

“…We have therefore synthesized new TSCD which have antiretroviral activity with the object of choosing those TSCD that have minimal effects on cell growth and the highest therapeutic index (TI) (Teitz et al, 1994). The mechanism of retroviral inhibition was shown to act at the level of viral mRNA translation (Ronen and Teitz, 1984;Ronen et al, 1985Ronen et al, , 1987. Recently, we have also described the selective repression by M-IBDET and A-IBDAT of v-abl-coded protein, an oncogene product associated with tyrosine kinase activity (Teitzet al, 1993).The efficacy ofthe TSCD was tested in feline T-Iymphocytes chronically infected with feline immunodeficiency virus (FIV).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Feline Immunodeficiency Virus Production and HIV Tat Activity by Thiosemicarbazone Derivatives

Teitz

Barko

Torten

et al. 1994

Antivir Chem Chemother

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Two thiosemicarbazone derivatives (TSCD), N-methylisatin-β-4′:4′-diethylthiosemicarbazone (M-IBDET) and N-allylisatin-β-4′:4-diallylthiosemicarbazone (A-IBDAT), were tested for their anti-feline immunodeficiency virus (FIV) activity in FL4/FIV cells. This cell line consists of feline T-lymphocytes chronically infected with FIV. FIV production in FL4/FIV cells was inhibited by M-IBDET and A-IBDAT. Virus inhibition was proportional to drug concentrations and time of treatment. The effective antiviral drug concentrations ranged from 0.06 to 0.64 μm for M-IBDET and from 0.45 to 8.7 μm for A-IBDAT. Tests performed to determine the therapeutic index (TI) value for each drug indicated TI values of 10 and 20 for M-IBDET and A-IBDAT, respectively. Continuous treatment of the cells with low doses of the drugs, given at constant time intervals, for a whole month succeeded in suppressing the chronic infection. Experiments directed towards understanding the mode of inhibition of FIV by TSCD indicated that A-IBDAT is involved in repression of the synthesis of the p24 structural protein of FIV. Examination of the possibility that the TSCD are also involved in suppression of the activity of HIV's tat regulatory protein showed a clear dose-responsive inhibition of HIV's tat-mediated transactivation by M-IBDET and A-IBDAT.

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“…Moreover, other thiosemicarbazones have antiviral activity against Japanese encephalitis virus (JEV) and West Nile virus in vitro and have also been found to completely inhibit JEV replication in vivo in a mouse model (33). Similarly, other studies have shown that methylisatin-␤-diethylthiosemicarbazone inhibits the replication of Moloney murine leukemia virus by interfering with the early phase of the viral life cycle (30) and that isatin-␤-thiosemicarbazone inhibits human immunodeficiency virus type 1 (HIV-1) replication in vitro (4).…”

Section: Bovine Viral Diarrhea Virus (Bvdv)mentioning

confidence: 99%

Inhibition of Bovine Viral Diarrhea Virus RNA Synthesis by Thiosemicarbazone Derived from 5,6-Dimethoxy-1-Indanone

Castro¹,

Fabián

Caputto

et al. 2011

J Virol

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In the present work, we described the activity of the thiosemicarbazone derived from 5,6-dimethoxy-1-indanone (TSC), which we previously characterized as a new compound that inhibits bovine viral diarrhea virus (BVDV) infection. We showed that TSC acts at a point of time that coincides with the onset of viral RNA synthesis and that it inhibits the activity of BVDV replication complexes (RCs). Moreover, we have selected five BVDV mutants that turned out to be highly resistant to TSC but still susceptible to ribavirin (RBV). Four of these resistant mutants carried an N264D mutation in the viral RNA-dependent RNA polymerase (RdRp). The remaining mutant showed an A392E mutation within the same protein. Some of these mutants replicated slower than the wild-type (wt) virus in the absence of TSC, whereas others showed a partial reversion to the wt phenotype over several passages in the absence of the compound. The docking of TSC in the crystal structure of the BVDV RdRp revealed a close contact between the indane ring of the compound and several residues within the fingers domain of the enzyme, some hydrophobic contacts, and hydrogen bonds with the thiosemicarbazone group. Finally, in the mutated RdRp from resistant BVDV, these interactions with TSC could not be achieved. Interestingly, TSC inhibited BVDV replication in cell culture synergistically with RBV. In conclusion, TSC emerges as a new nonnucleoside inhibitor of BVDV RdRp that is synergistic with RBV, a feature that turns it into a potential compound to be evaluated against hepatitis C virus (HCV).

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Effect of N-methylisatin-β-4′:4′-diethylthiosemicarbazone on intracellular Moloney leukemia virus constituents

Cited by 15 publications

References 13 publications

Semicarbazonas e tiossemicarbazonas: o amplo perfil farmacológico e usos clínicos

Semicarbazonas e tiossemicarbazonas: o amplo perfil farmacológico e usos clínicos

Inhibition of Feline Immunodeficiency Virus Production and HIV Tat Activity by Thiosemicarbazone Derivatives

Inhibition of Bovine Viral Diarrhea Virus RNA Synthesis by Thiosemicarbazone Derived from 5,6-Dimethoxy-1-Indanone

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