Optimization of piperazine-derived ureas privileged structures for effective antiadenovirus agents
Articolo
Data di Pubblicazione:
2020
Citazione:
Optimization of piperazine-derived ureas privileged structures for effective antiadenovirus agents / S. Mazzotta, J.A. Marrugal-Lorenzo, M. Vega-Holm, A. Serna-Gallego, J. Alvarez-Vidal, J. Berastegui-Cabrera, J. Perez del Palacio, C. Diaz, F. Aiello, J. Pachon, F. Iglesias-Guerra, J.M. Vega-Perez, J. Sanchez-Cespedes. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - 185(2020), pp. 111840.1-111840.23. [10.1016/j.ejmech.2019.111840]
Abstract:
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.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
Adenovirus; Antiviral drug; Privileged structures; Thiourea/urea piperazine derivatives; A549 Cells; Adenoviruses, Human; Antiviral Agents; Cell Line; Cell Survival; DNA Replication; Dose-Response Relationship, Drug; Humans; Microbial Sensitivity Tests; Molecular Structure; Piperazines; Structure-Activity Relationship; Urea
Elenco autori:
S. Mazzotta, J.A. Marrugal-Lorenzo, M. Vega-Holm, A. Serna-Gallego, J. Alvarez-Vidal, J. Berastegui-Cabrera, J. Perez del Palacio, C. Diaz, F. Aiello, J. Pachon, F. Iglesias-Guerra, J.M. Vega-Perez, J. Sanchez-Cespedes
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