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

Eur J Med Chem. 2020 Jan 1:185:111840. doi: 10.1016/j.ejmech.2019.111840.

Sarah Mazzotta ¹, José Antonio Marrugal-Lorenzo ², Margarita Vega-Holm ³, Ana Serna-Gallego ², Jaime Álvarez-Vidal ⁴, Judith Berastegui-Cabrera ², José Pérez Del Palacio ⁵, Caridad Díaz ⁵, Francesca Aiello ⁶, Jerónimo Pachón ⁷, Fernando Iglesias-Guerra ⁴, José Manuel Vega-Pérez ⁴, Javier Sánchez-Céspedes ⁸

Affiliations

1 Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Seville, E-41071, Seville, Spain; Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036, Arcavacata di Rende, CS, Italy.
2 Clinical Unit of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain.
3 Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Seville, E-41071, Seville, Spain. Electronic address: mvegaholm@us.es.
4 Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Seville, E-41071, Seville, Spain.
5 Fundación Medina, Parque Tecnológico de Ciencias de la Salud, E-18016, Granada, Spain.
6 Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036, Arcavacata di Rende, CS, Italy.
7 Clinical Unit of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain; Department of Medicine, University of Seville, E-41009, Seville, Spain.
8 Clinical Unit of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain. Electronic address: jsanchez-ibis@us.es.

PMID: 31711794 DOI: 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.

Keywords

Adenovirus; Antiviral drug; Privileged structures; Thiourea/urea piperazine derivatives.

Name
Email *

	Sorry, but the email address you supplied was invalid.