Optimization of piperazine-derived ureas privileged structures for effective antiadenovirus agents

• Published in: European journal of medicinal chemistry Vol. 185; p. 111840
• Main Authors: Mazzotta, Sarah, Marrugal-Lorenzo, José Antonio, Vega-Holm, Margarita, Serna-Gallego, Ana, Álvarez-Vidal, Jaime, Berastegui-Cabrera, Judith, Pérez del Palacio, José, Díaz, Caridad, Aiello, Francesca, Pachón, Jerónimo, Iglesias-Guerra, Fernando, Vega-Pérez, José Manuel, Sánchez-Céspedes, Javier
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 01.01.2020; Elsevier
• Subjects: A549 Cells; Adenovirus; Adenoviruses, Human - drug effects; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Antiviral drug; Cell Line; Cell Survival - drug effects; Chemistry, Medicinal; DNA Replication - drug effects; Dose-Response Relationship, Drug; Humans; Life Sciences & Biomedicine; Microbial Sensitivity Tests; Molecular Structure; Pharmacology & Pharmacy; Piperazines - chemical synthesis; Piperazines - chemistry; Piperazines - pharmacology; Privileged structures; Science & Technology; Structure-Activity Relationship; Thiourea/urea piperazine derivatives; Urea - analogs & derivatives; Urea - chemistry; Urea - pharmacology; Thiourea/urea piperazine derivatives; Privileged structures; Antiviral drug; Adenovirus; IMMUNOCOMPETENT; ALPHA-AMANITIN; IN-VITRO; REPLICATION; DISRUPTION; INFECTION; GENE-TRANSFER; INHIBITORS; DERIVATIVES; ACQUIRED ADENOVIRUS PNEUMONIA
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2019.111840

In recent years, human adenovirus (HAdV) infections have shown a high clinical impact in both immunosuppressed and immunocompetent patients. The research into specific antiviral drugs for the treatment of HAdV infections in immunocompromised patients constitutes a principal objective for medicinal chemistry due to the lack of any specific secure drug to treat these infections. In this study, we report a small-molecule library (67 compounds) designed from an optimization process of piperazine-derived urea privileged structures and their biological evaluation: antiviral activity and cytotoxicity. The active compounds selected were further evaluated to gain mechanistic understanding for their inhibition. Twelve derivatives were identified that inhibited HAdV infections at nanomolar and low micromolar concentrations (IC50 from 0.6 to 5.1 μM) with low cytotoxicity. In addition, our mechanistic assays suggested differences in the way the derivatives exert their anti-HAdV activity targeting transcription, DNA replication and later steps in the HAdV replication cycle. Furthermore, eight of the 12 studied derivatives blocked human cytomegalovirus (HCMV) DNA replication at low micromolar concentrations. The data provided herein indicates that the 12 thiourea/urea piperazine derivatives studied may represent potential lead compounds for clinical evaluation and development of new anti-HAdV drugs. [Display omitted] •Design, synthesis and evaluation of a small library through an optimization process.•The synthesis was carried out following a short and high yielded methodology.•Twelve derivatives were identified to inhibit HAdV replication (IC50 from 0.6 to 5.1 μM) with low cytotoxicity.•They targeted different steps on the HAdV replicative cycle.•Six compounds have been selected for further in vivo studies in Syriam Hamster model.