RESUMO
In this work, several ribavirin analogues were synthesized and incorporated into a multivalent arrangement. Both were subsequently modified by the addition of polyhydroxylated residues. Their antiviral activity was tested against Junín virus, etiological agent responsible of Argentine hemorrhagic fever. Some compounds inhibited Junín virus in the range of 13.2-389.1⯵M. Two modified ribavirin analogues presented an effective concentration comparable to ribavirin but with a higher selectivity index.
Assuntos
Antivirais/farmacologia , Vírus Junin/efeitos dos fármacos , Ribavirina/análogos & derivados , Células A549 , Animais , Chlorocebus aethiops , Humanos , Células VeroRESUMO
Twenty-seven brassinosteroid derivatives were tested for antiviral activity against measles virus (MV) via a virus-yield reduction assay. Compounds 6b [(22S,235)-3beta-bromo-5alpha,22,23-trihydroxystigmastan-6-one], 1d [(22R,23R)-2alpha,3alpha,22,23-tetrahydroxy-beta-Homo-7-oxa-stigmastan-6-one], 8a [(22R,23R)-3beta-fluoro-22,23-dihydroxystigmastan-6-one], 9b [(22S,23S)-3beta-fluoro-5alpha,22,23-trihydroxystigmastan-6-one] and 10b [(22S,23S)-5alpha-fluor-3beta,22,23-trihydroxystigmastan-6-one], with selectivity indexes (SI) of 40, 57, 31, 37 and 53, are the derivatives with good antiviral activity against MV. These SI values are higher than those obtained with ribavirin (used as reference drug). A comparative analysis of 50% cytotoxic concentration (CC50) values, using confluent non-growing cells, gives and indication of structure-activity relationship. According to their degree of cytotoxicity the compounds were divided in three groups: low, intermediate and high cytotoxicity. By observing the chemical structures of compounds belonging to the first group we can see that less cytotoxic activities are related to the presence of a 3beta-hydroxy group on C-3 (ring A) and a double bond between C-22 and C-23 (side chain). The replacement of a 5alpha-hydroxy group by a 5alpha-fluoro group enhances cytotoxicity. Halogenated brassinosteroid derivatives in C-3 position are more cytotoxic than those with an acetoxy group in the same position. For compounds 1d, 6b, 10b and ribavirin, cytotoxicity measurements were also done with replicating cells; CC50 values were low, but they still competed favourably with ribavirin against MV.
Assuntos
Antivirais/farmacologia , Vírus do Sarampo/efeitos dos fármacos , Ribavirina/análogos & derivados , Esteroides Heterocíclicos/farmacologia , Animais , Antivirais/síntese química , Chlorocebus aethiops , Efeito Citopatogênico Viral , Formazans , Humanos , Concentração Inibidora 50 , Vírus do Sarampo/crescimento & desenvolvimento , Ribavirina/síntese química , Ribavirina/farmacologia , Esteroides Heterocíclicos/síntese química , Relação Estrutura-Atividade , Sais de Tetrazólio , Células Vero , Replicação Viral/efeitos dos fármacosRESUMO
Subcutaneous injections of ribavirin into guinea pigs infected intraperitoneally or intracerebrally with Junin virus significantly increased the mean time to death but did not enhance survival of the animals. We found similar results with tributylribavirin. Virus replication was delayed, but not prevented, in ribavirin-treated infected guinea pigs. The animals usually died with high virus titers in their brains and frequently were paralyzed.