In search of new antiviral targets: Design and synthesis of new inhibitors of ZIKV Mtase and potential inhibitors of IMPDH

Viral infections are a leading cause of death worldwide. In 2016, WHO declared a public health emergency due to the spread of the Zika virus (ZIKV). In addition, the recent link between this infection and the clustered incidence of microcephaly and other neurological disorders represents a public health emergency of international significance. An effective strategy to address this emergency could be the identification and development of new antiviral agents against the NS5 protein of ZIKV that specifically target the methyltransferase (Mtase) domain. When this enzyme is blocked, the virus cannot cap the RNA and evade restriction by the host's innate immune system, preventing it from replicating. In this work, a new series of antiviral compounds that are easy and reproducible to prepare were designed and synthesized. They were endowed with antiviral activity on ZIKAV-infected cells and the most active of them were screened for their absorption, distribution, metabolism, and excretion (ADME) properties in vitro. In the second part of this work, a new compound, a potential inhibitor of the enzyme IMPDH, was designed and synthesized: IMPDH plays an important role in antiviral and anticancer processes as it catalyzes the rate-limiting step in the de novo biosynthesis of guanine nucleotides and can therefore be considered a strategic target for the development of novel antiviral compounds. The last part of the thesis explains the work carried out during the stay abroad at RWTH Aachen University, where the synthesis of an S-allenylsulfoximine derivative was studied: thanks to the allenyl group these compounds can be very useful in organic chemistry when it comes to the incorporation of new units and also, thanks to the sulfoximine moiety can also be used in pharmaceutical chemistry by taking advantage of their important properties.