Design, synthesis and biological evaluation of new broad-spectrum antivirals active against enteroviruses and related diseases

Abstract

Enteroviruses (EVs)are small, single-stranded, positive-sense RNA viruses belonging to the Picornaviridae family and responsible for a great variety of clinical manifestations, especially in young children, which may result in life-threatening neurological complications. Moreover the causal role of enteroviruses as trigger of acute exacerbations in chronic pulmonary diseases has been widely demonstrated. No antiviral drugs have been approved for the treatment of EV infections, so treatment is currently limited to symptomatic and supportive care. Clearly, there is a strong need for broad-spectrum antivirals (BSAs) as a rapid defence strategy against enterovirus infections and virus-related exacerbations. The aim of this PhD project was to identify new small molecules with broad-spectrum antiviral activity against enteroviruses. We decided to follow both virus- and host-targeting approaches, currently explored for the development of broad-spectrum antivirals. We first focused our attention on impairing enterovirus replication by targeting the viral polymerase, considered one of the most promising targets in antiviral drug discovery and a suitable strategy for the development of BSAs. Then we studied the inhibition of the host lipid kinase PI4KIIIβ, critical for mediating the replication of different enteroviruses. Considering the under-explored connection between EVs and pulmonary exacerbation in cystic fibrosis (CF) patients, we discovered a new class of compounds with broad-spectrum activity against representative enteroviruses (by targeting PI4KIIIβ) and correctors of the CFTR F508del folding defect responsible for >90% of CF cases. A series of interesting compounds with promising antiviral activity and PI4KIIIβ inhibitory potency were identified. Then considering the chemical scaffold of the recently identified PI4KIIIβ inhibitors and with the final aim to obtain substituted [1,2,4]triazolo[4,3-a]pyridines/pyrazinesas novel antivirals,we developed a fast and versatile synthesis of the precursor heteroaryl-hydrazones, by combining organo/metal catalysis and microwave assisted technology.This protocol also allowed us to identify novel heteroaryl-hydrazones as potential anti-Parkinson’s agents targeting the host kinase LRRK2.