Synthesis and assessment of 4-aminotetrahydroquinazoline derivatives as tick-borne encephalitis virus reproduction inhibitors

Abstract

Tick-borne encephalitis virus (TBEV) belonging to Flavivirus genus causes severe infection in humans. The search for therapeutically relevant compounds targeting TBEV requires the exploration of novel chemotypes. A versatile synthesis of previously unknown 4-aminopyrimidines and 4-aminopyrimidine N-oxides based on a fluorosubstituted heterocyclic core is described. A representative series of 4-aminotetrahydroquinazoline derivatives, containing aliphatic and aromatic substituents as well as the adamantane framework, was obtained and their activity against tick-borne encephalitis virus reproduction was studied. Nine compounds were found to inhibit TBEV entry into the host cells. A bulky hydrophobic adamantyl group was identified to be important for the antiviral activity. The developed synthetic route allowed an easy access to a consistent compound library for further structure-activity relationship studies.

Selective Inhibition of Enterovirus A Species Members’ Reproduction by Furano[2, 3‐d]pyrimidine Nucleosides Revealed by Antiviral Activity Profiling against (+)ssRNA Viruses

“…Antiviral activity and cytotoxicity were determined using previously described methods for TBEV (plaque reduction test) and enteroviruses (cytopathic effect inhibition test). Enterovirus activity screening was performed against enterovirus A71 (EVA71), coxsackievirus B1 (CVB1), and poliovirus (PV1); active compounds were additionally assessed against the remaining viruses.…”

EAN consensus review on prevention, diagnosis and management of tick‐borne encephalitis

“…Some drugs have been shown to exert an antiviral effect in murine TBE models [219][220][221][222]. Antiviral activity of several compounds against TBE in experiments in cell cultures and in vitro experiments to inhibit replication of TBEV by RNA interference may lead to prospects for further trials [223][224][225][226][227][228][229][230].…”

Probing chemical space of tick‐borne encephalitis virus reproduction inhibitors with organoselenium compounds

“…Cytopathic effect inhibition test against members of Enterovirus genus was performed as described previously . In brief, eight twofold dilutions of stock solutions of the compounds in four replicates were prepared in 2 × EMEM medium (Chumakov FSC R&D IBP RAS) to obtain a final concentration series starting from 62.5 µM.…”

“…Structural proteins are responsible for the virion structure and stability, virus entry, virion assembly and exit. Several studies showed the possibility to suppress TBEV reproduction in cells via interfering with the entry process . Non‐structural proteins mainly orchestrate the process of virus replication.…”