2-Aminothiazolones as Anti-HIV Agents That Act as gp120-CD4 Inhibitors

Tiberi, Marika; Tintori, Cristina; Ceresola, Elisa Rita; Fazi, Roberta; Zamperini, Claudio; Calandro, Pierpaolo; Franchi, Luigi; Selvaraj, Manikandan; Botta, Lorenzo; Sampaolo, Michela; Saita, Diego; Ferrarese, Roberto; Clementi, Massimo; Canducci, Filippo; Botta, Maurizio

doi:10.1128/aac.02739-13

Cited by 13 publications

(4 citation statements)

References 44 publications

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“…Twenty thousand TZM-bl cells/well were seeded in 96-well plates in complete DMEM supplemented with 30 μg/mL DEAE-dextran (Sigma-Aldrich). Three hundred times the 50% tissue culture infective dose (TCID50)/mL of each strain was pretreated for 1 h at 37°C with six serial dilutions (20000 nM to 3.2 nM) of each compound and then added to the cells, as previously described [ 29 – 32 ]. Vehicle (0.1% dimethyl sulfoxide [DMSO])-treated cells served as a negative control.…”

Section: Methodsmentioning

confidence: 99%

Rhodanine derivatives as potent anti-HIV and anti-HSV microbicides

et al. 2018

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Although highly active antiretroviral therapies (HAART) remarkably increased life expectancy of HIV positive people, the rate of novel HIV-1 infections worldwide still represent a major concern. In this context, pre-exposure prophylaxis (PrEP) approaches such as vaginal microbicide gels topically releasing antiretroviral drugs, showed to have a striking impact in limiting HIV-1 spread. Nevertheless, the co-presence of other genital infections, particularly those due to HSV-1 or 2, constitute a serious drawback that strongly limits the efficacy of PrEP approaches. For this reason, combinations of different compounds with mixed antiviral and antiretroviral activity are thoroughly investigated Here we report the synthesis and the biological evaluation of a novel series of rhodanine derivatives, which showed to inhibit both HIV-1 and HSV-1/2 replication at nanomolar concentration, and were found to be active also on acyclovir resistant HSV-2 strains. The compounds showed a considerable reduction of activity in presence of serum due to a high binding to serum albumin, as determined through in vitro ADME evaluations. However, the most promising compound of the series maintained a considerable activity in gel formulation, with an EC50 comparable to that obtained for the reference drug tenofovir. Moreover, the series of compounds showed pharmacokinetic properties suitable for topical formulation, thus suggesting that the novel rhodanine derivatives could represent effective agents to be used as dual anti HIV/HSV microbicides in PrEP approaches.

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Section: Methodsmentioning

confidence: 99%

Rhodanine derivatives as potent anti-HIV and anti-HSV microbicides

et al. 2018

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“…For this reason, an env-pseudotyped virus (REJO4541 clone 67) was used. Time of addition (TOA) experiment was performed as previously described with minor modifications [ 83 ]. 40000 TZM-bl cells/well in a 96-multiwell plate were infected with 1500 X the TCID50 per mL of the env-pseudotyped HIV-1 virus in complete medium supplemented with DEAE-dextran (Sigma–Aldrich, 30 mg/mL).…”

Section: Methodsmentioning

confidence: 99%

Prenylated phloroglucinols from Hypericum scruglii, an endemic species of Sardinia (Italy), as new dual HIV-1 inhibitors effective on HIV-1 replication

Sanna

Scognamiglio

Fiorentino³

et al. 2018

PLoS ONE

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In a search for new potential multitarget anti-HIV compounds from natural products, we have identified in Hypericum scruglii, an endemic and exclusive species of Sardinia (Italy), a potent plant lead. The phytochemical study of the hydroalcoholic extract obtained from its leaves led to the isolation of its most abundant secondary metabolites, belonging to different chemical classes. In particular, three phloroglucinols derivatives were identified, confirming their significance as chemotaxonomic markers of the Hypericum genus. Among them, the 3-(13-hydroxygeranyl)-1-(2'-methylbutanoyl)phloroglucinol was reported here for the first time. All six isolated compounds have been evaluated firstly for the inhibition of both Human Immunodeficiency Virus type 1 (HIV-1) Reverse Transcriptase (RT)-associated DNA Polymerase (RDDP) and Ribonuclease H (RNase H) activities, for the inhibition of HIV-1 integrase (IN) in biochemical assays, and also for their effect on viral replication. Among the isolated metabolites, three phloroglucinol derivatives and quercitrin were effective on both RT-associated RDDP and RNase H activities in biochemical assays. The same active compounds affected also HIV-1 IN strand transfer function, suggesting the involvement of the RNase H active site. Furthermore, phloroglucinols compounds, included the newly identified compound, were able to inhibit the HIV-1 replication in cell based assays.

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“…Time‐of‐addition (TOA) assay : The TOA experiment was performed as previously described with minor modifications, with use of a single cycle assay and the pseudotype virus REJO4541 clone 67. For the TOA assay, 40 000 TZM‐bl cells/well in a 96‐multiwell plate were infected with 1500× the TCID 50 per mL of the env‐pseudotyped HIV‐1 virus in complete medium supplemented with diethylaminoethyl (DEAE)‐dextran (Sigma–Aldrich, 30 μg mL −1 ).…”

Section: Figurementioning

confidence: 99%

Natural Product Kuwanon‐L Inhibits HIV‐1 Replication through Multiple Target Binding

et al. 2017

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In recent years many advances have been made in the fight against HIV-1 infection. However, the lack of a vaccine, together with the increasing resistance to the highly active anti-retroviral therapy (HAART), make HIV-1 infection still a serious global emergency. Thus, new compounds with original modes of action are continuously required, and natural products have ever been a very interesting class of pharmacologically active molecules. Some of them have been used since ancient times against viral infections. Here we present a work in which we suggest that kuwanon-L, a natural product active as an HIV-1 integrase (IN) inhibitor, might exert its overall antiviral activity through binding to multiple viral targets. Specific enzymatic tests, together with a time-of-addition (TOA) experiment, support our hypothesis of binding both to IN and to reverse transcriptase (RT). Overall, this compound can be considered an attractive lead for the development of new classes of antiviral agents able to overcome the problem of resistance, due to its ability to exert its action by binding simultaneously to multiple viral targets.

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2-Aminothiazolones as Anti-HIV Agents That Act as gp120-CD4 Inhibitors

Cited by 13 publications

References 44 publications

Rhodanine derivatives as potent anti-HIV and anti-HSV microbicides

Rhodanine derivatives as potent anti-HIV and anti-HSV microbicides

Prenylated phloroglucinols from Hypericum scruglii, an endemic species of Sardinia (Italy), as new dual HIV-1 inhibitors effective on HIV-1 replication

Natural Product Kuwanon‐L Inhibits HIV‐1 Replication through Multiple Target Binding

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