A way to broad spectrum antiviral agents: small molecules based on piperazine core as potential flaviviridae NS3 protease inhibitors

Flaviviridae virus family is subdivided into four genera namely, Flavivirus, Hepacivirus, Pegivirus and Pestivirus [1,2]. The incidence of Flavivirus infection has grown significantly, with approximately 400 million people infected annually [3] and widely distributed as consequence of globalization and climate changes, causing public health problems worldwide [4,5]. Currently, there are no effective drugs available to treat most of these infections. All genera of the Flaviviridae family show similarities in the organization of the viral genome, which is characterized by a single-stranded positive-sense RNA molecule. The whole viral genome is translated into a viral polyprotein, which is further processed by both host and viral proteases into 9 to 12 mature proteins, consisting of structural and nonstructural (NS) proteins [1,6]. The NS proteins participate in the replication of the RNA genome, virion assembly and interaction with innate host immune response [7]. As a result, these viral proteins represent relevant targets for the development of novel antiviral therapies. Among these, the NS32B proteases play an important role in the virus life cycle, making them attractive targets for antiviral drug discovery [8].Taking advantage of our previous research focused on the development of effective antiviral agents based on piperazine backbone [9], we have recently described two piperazine-derived compounds as promising and non-cytotoxic broad spectrum anti Flavivirus agents [10].The compounds were designed using a privileged structure-based approach, and their antiviral properties were determined by a live virus cell based phenotypic assay against ZIKV and DENV [11], leading to the identification of these promising lead compounds. Based on these important results, this study focuses on the design and synthesis of a small library of molecules acting as potential NS3 protease inhibitors. Our approach involves an optimization process aimed at preserving the molecular complexity of these compounds, which includes three aromatic/aliphatic rings linked by amide and urea/sulfonamide functions. Due to the relevance of the piperazine ring in biological activity of these compounds [12], we decided to retain it as the central core.The focus of this research is to improve the antiviral activity against both viruses and simultaneously obtaining non-cytotoxicity products associated with these lead compounds.