New 4-Acyl-1-phenylaminocarbonyl-2-phenylpiperazine Derivatives as Potential Inhibitors of Adenovirus Infection. Synthesis, Biological Evaluation, and Structure–activity Relationships

Abstract

The search for human adenovirus (HAdV)-specific antiviral drugs for the treatment of HAdV infections in immunocompromised patients continues to be a challenging goal for medicinal chemistry. Here, we report the synthesis, biological evaluation, and structure-activity relationships of a small molecules library. We have identified six phenylpiperazine derivatives that significantly inhibited HAdV infection. These six compounds showed the capacity to block HAdV and, in addition, human cytomegalovirus (HCMV) replications at low micromolar concentration, with little or no cytotoxicity. On the basis of our biological studies, these molecules block HAdV and HCMV infections in different phases of their life cycle, providing potential candidates for the development of a new family of antiviral drugs for the treatment of infections by DNA viruses.

Repositioning salicylanilide anthelmintic drugs to treat adenovirus infections

“…Based on previous works where piperazine derivatives and nucleotide and nucleoside analogues showed antiviral activity against multiple dsDNA virus including cytomegalovirus (HCMV) and HAdV 24,25 , we evaluated the inhibitory activity of NIC, OXY and RAF on HCMV DNA replication. The presence of these anthelmintic drugs generated significant reductions in the quantification of total HCMV DNA 72 h after infection of MRC-5 cells (Fig.…”

“…Then, cells were incubated for 72 h at 37 °C and 5% CO 2 and HCMV DNA was purified from the cell lysate using the QIAamp DNA Mini Kit (Qiagen, Valencia, CA) following the manufacturer’s instructions. Real-time PCR primers, mixtures and protocols were the same as previously reported 25 .…”

Recent Advances in Novel Antiviral Therapies against Human Adenovirus

“…Among other categories of small molecules with antiviral activity against HAdV, piperazine-derived compounds have shown promise in several investigations [ 135 , 136 ]. A trisubstituted piperazin-2-one derivative was identified in a small molecule screen (further discussed in Section 6.6 ), and inhibited viral DNA replication at low micromolar concentrations, with minimal cytotoxicity [ 135 ].…”

Identification of human adenovirus replication inhibitors from a library of small molecules targeting cellular epigenetic regulators

“…Several research groups have performed small molecule screens to identify novel anti-HAdV compounds ( Duffy et al, 2013 ; Grosso et al, 2017 ; Hartline et al, 2018 ; Marrugal-Lorenzo et al, 2018 ; Sanchez-Cespedes et al, 2016 ; Wang et al, 2018 ). To facilitate and simplify high-throughput screening for anti-HAdV compounds, we recently developed a wildtype-like HAdV-5 reporter construct that contained the red fluorescent protein (RFP) gene under regulation of the HAdV major late promoter (MLP), such that the level of RFP expression correlated with viral late gene expression and DNA replication ( Saha and Parks, 2019 ).…”