RESUMO
New chiral purinyl and 8-azapurinyl carbanucleoside derivatives based on indanol were synthesized from commercial available (1S,2S)-trans-1-amino-2-indanol and (1R,2R)-trans-1-amino-2-indanol using a linear methodology. The antiviral activity and cytotoxicity of these compounds were evaluated against herpes simplex virus type 1 (HSV-1) in Vero cells, bovine viral diarrhea virus (BVDV) in Mardin-Darby bovine kidney (MDBK) cells and hepatitis B virus (HBV) in HepG2 2.2.15 cell line. Three compounds, showed an inhibition of the HBsAg levels similar to reference drug lamivudine. One chloropurinyl nucleoside, derived from the cis-1-amino-2-indanol, was cytotoxic on MDBK cells and it could be a lead for developing anticancer agents.
Assuntos
Antivirais/química , Antivirais/farmacologia , Indanos/química , Indanos/farmacologia , Nucleosídeos/química , Nucleosídeos/farmacologia , Animais , Antivirais/síntese química , Doença das Mucosas por Vírus da Diarreia Viral Bovina/tratamento farmacológico , Bovinos , Linhagem Celular , Chlorocebus aethiops , Vírus da Diarreia Viral Bovina/efeitos dos fármacos , Cães , Células Hep G2 , Hepatite B/tratamento farmacológico , Vírus da Hepatite B/efeitos dos fármacos , Herpes Simples/tratamento farmacológico , Herpesvirus Humano 1/efeitos dos fármacos , Humanos , Indanos/síntese química , Nucleosídeos/síntese química , Estereoisomerismo , Células VeroRESUMO
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).
Assuntos
Antivirais/farmacologia , Vírus da Diarreia Viral Bovina/efeitos dos fármacos , Indanos/farmacologia , RNA Viral/biossíntese , Tiossemicarbazonas/farmacologia , Replicação Viral/efeitos dos fármacos , Substituição de Aminoácidos , Animais , Antivirais/química , Linhagem Celular , Vírus da Diarreia Viral Bovina/fisiologia , Farmacorresistência Viral , Humanos , Indanos/química , Modelos Moleculares , Mutação de Sentido Incorreto , Estrutura Terciária de Proteína , RNA Polimerase Dependente de RNA/genética , RNA Polimerase Dependente de RNA/metabolismo , Ribavirina/farmacologia , Tiossemicarbazonas/química , Proteínas Virais/genética , Proteínas Virais/metabolismoRESUMO
The antiviral activities of lamivudine (3TC; 2',3'-dideoxy-3'-thiacytidine) and six 5'-O-carbonates of 3TC were determined by inhibition of hepatitis B virus (HBV) replication in HepG2 2.2.15 cells. HBV DNA in cell supernatants was quantified by real-time polymerase chain reaction (PCR). The results showed that 3TC-Etha was six times more active than 3TC and that 3TC-Buta, 3TC-Hexa and 3TC-Octa were approximately three times more active than 3TC. In contrast, 3TC-Penta and 3TC-Metha showed anti-HBV activity similar to that of the parent compound 3TC. In conclusion, 5'-O-carbonates of 3TC appear to be promising candidates as anti-HBV compounds. This modification could optimise the use of 3TC, a well-tolerated, effective and inexpensive drug, in monotherapy or combined therapy for chronic HBV infections as well as human immunodeficiency virus (HIV)/HBV co-infections.