Synthesis and anti-HSV-1 activity of quinolonic acyclovir analogues.
Several 1-[(2-hydroxy-ethoxy)methyl]-3-carbethoxy-4(1H)quinolones (2a-l) and l-[(2-hydroxy-ethoxy)methyl]-4(1H)quinolone-3-carboxylic acids (3a-j and 3l) were synthesized and 2a-j, 2l and 3a-j, 3l were evaluated against herpes simplex virus type 1 (HSV-1), employing a one-pot reaction: silylation of the desired quinolone (BSTFA 1% TMCS) followed by equimolar amount addition of 1,3-dioxolane, chlorotrimethylsilane and KI, at room temperature. The acyclonucleosides 2a-l were obtained in 40-77% yields. The esters 2a-j and 2l were subsequently converted into the corresponding hydroxyacids 3 in 40-70% yields. Attempts of hydrolysis of 2k produced only a mixture of degradation products. Antiviral activity of 2 and 3 on HSV-1 virus infection was assessed by the virus yield assay. Except for compounds 2i and 3e, the acyclonucleosides were found to reduce the virus yield by 70-99% at the concentration of 50 microM, being the acids, in general, more effective inhibitors than their corresponding esters. Compounds 3j and 2d exhibited antiviral activity against HSV-1 virus with EC50 of 0.7+/-0.04 and 0.8+/-0.09 microM, respectively. Both compounds were not toxic towards the Vero cell line.
Lucero
Bianca d'A
Bd
Universidade Federal Fluminense, Instituto de Química, Departamento de Química Orgânica, Outeiro de São João Batista s/no, Centro, Niterói, CEP 24210-150, Rio de Janeiro, Brazil.
Gomes
Claudia Regina B
CR
Frugulhetti
Izabel Christina de P P
IC
Faro
Letícia V
LV
Alvarenga
Lise
L
de Souza
Maria Cecília B V
MC
de Souza
Thiago M L
TM
Ferreira
Vitor F
VF
D000212:Acyclovir / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002522:Chlorocebus aethiops; D018259:Herpesvirus 1, Human / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014709:Vero Cells / Q000187:drug effects / Q000821:virology
D000998:Antiviral Agents; D000212:Acyclovir