Novel anti-adenovirus agents based on aminoglycerol and piperazine scaffolds: design, synthesis and in vitro biological evaluation

Abstract

HAdV is a non-enveloped virus that has progressively been recognized as significant viral pathogen. It traditionally causes self-limited respiratory, gastrointestinal and conjunctival infections, mainly in immunocompromised patients. HAdV-induced infections are associated with significant morbidity and mortality, both in immunosuppressed and otherwise healthy individuals. At present, there are no effective and specific antiviral drugs approved for HAdV infections. The current and non-specific therapeutic options provide no satisfactory results in terms of efficacy and safety. Cidofovir is the drug of choice for the treatment of severe HAdV infections, but display low oral bioavailability and nephrotoxicity that limit its use in therapy. Consequently, there is an urgent need to identify new anti-HAdV agents with suitable therapeutic index. In this work, we report the design, synthesis, structural characterization and biological evaluation of new compound libraries as novel anti-HAdV infection inhibitors. Piperazine and aminoalcohols scaffolds were selected to generate new molecules, introducing most common functions present in reported anti-adenovirus agents. A set of piperazine derivatives (67 compounds) were designed through an optimization process starting from our previous work. Twelve derivatives were identified with significant inhibition of HAdV infections at nanomolar and low micromolar concentrations (IC50 from 0.6 μM to 5.1 μM) with low or no cytotoxicity. These compounds were selected for further biological analysis in order to explore their potencial mechanism of action. Our studies suggested that most active compounds inhibited HAdV replicative cycle through different mechanisms of action. A small library of serinol derivatives (37 compounds) was designed and synthesized in order to evaluate acyclic scaffolds and develop new effective anti-HAdV agents. Four compounds inhibited HAdV infection in a dose-dependent manner, reducing HAdV infection at low micromolar concentrations (from 2.82 to 5.35 M). Their IC50 values were lower compared to that of cidofovir, the current drug of choice. All compounds significantly reduced HAdV DNA replication process. Finally, a collection of 3-amino-1,2-propanediol (55 compounds) derivatives was designed to further explore the potential of aminoalcohol scaffolds in providing effective antiviral agents. Different synthetic methodologies were employed for the introduction of the acyl/triazole functions at primary or secondary position of the aminoalcohol skeleton. Six derivatives demonstrated a significant inhibition of HAdV infection and displayed IC50 values at low micromolar concentration (2.47-4.19 μM). At present these compounds are being submitted to further biological assays in order to select compounds with suitable selectivity index and investigate their potential mechanism of action. The new data indicate that these new scaffolds may represent a potential tool useful for the development of effective anti-HAdV drugs.