RESUMO
AIDS-related cancer diseases are malignancies with low incidence on healthy people that affect mostly subjects already immunocompromised. The connection between HIV/AIDS and these cancers has not been established yet, but a weakened immune system is certainly the main cause. We envisaged the possibility to screen a small library of compounds synthesized in our laboratory against opportunistic tumors mainly due to HIV infection like Burkitt's Lymphoma. From cellular assays and gene expression analysis we identified two promising compounds. These derivatives have the dual action required inhibiting HIV replication in human TZM-bl cells infected with HIV-1 NL4.3 and showing cytotoxic activity on human colon HT-29 and breast adenocarcinoma MCF-7 cells. In addition, preclinical in vitro adsorption, distribution, metabolism, and excretion studies highlighted a satisfactory pharmacokinetic profile.
Assuntos
Antirretrovirais/química , Antirretrovirais/metabolismo , Antirretrovirais/farmacologia , Antirretrovirais/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , HIV-1/efeitos dos fármacos , Células HT29 , Humanos , Células MCF-7 , Microssomos Hepáticos/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Telomerase/genética , Telomerase/metabolismoRESUMO
We report here the synthesis of 2-aminothiazolones along with their biological properties as novel anti-HIV agents. Such compounds have proven to act through the inhibition of the gp120-CD4 protein-protein interaction that occurs at the very early stage of the HIV-1 entry process. No cytotoxicity was found for these compounds, and broad antiviral activities against laboratory strains and pseudotyped viruses were documented. Docking simulations have also been applied to predict the mechanism, at the molecular level, by which the inhibitors were able to interact within the Phe43 cavity of HIV-1 gp120. Furthermore, a preliminary absorption, distribution, metabolism, and excretion (ADME) evaluation was performed. Overall, this study led the basis for the development of more potent HIV entry inhibitors.
Assuntos
Fármacos Anti-HIV/farmacologia , Antígenos CD4/efeitos dos fármacos , Proteína gp120 do Envelope de HIV/antagonistas & inibidores , Inibidores da Fusão de HIV/farmacologia , HIV-1/efeitos dos fármacos , Fármacos Anti-HIV/química , Antígenos CD4/química , Antígenos CD4/metabolismo , Linhagem Celular , Proteína gp120 do Envelope de HIV/metabolismo , Inibidores da Fusão de HIV/química , Humanos , Simulação de Acoplamento Molecular , Ligação ProteicaRESUMO
Viral infections are an important cause of death worldwide. Unfortunately, there is still a lack of antiviral drugs or vaccines for a large number of viruses, and this represents a remarkable challenge particularly for emerging and re-emerging viruses. For this reason, the identification of broad spectrum antiviral compounds provides a valuable opportunity for developing efficient antiviral therapies. Here we report on a class of rhodanine and thiobarbituric derivatives displaying a broad spectrum antiviral activity against seven different enveloped viruses including an HSV-2 acyclovir resistant strain with favorable selectivity indexes. Due to their selective action on enveloped viruses and to their lipid oxidation ability, we hypothesize a mechanism on the viral envelope that affects the fluidity of the lipid bilayer, thus compromising the efficiency of virus-cell fusion and preventing viral entry.