The vast majority of viruses causing human and animal diseases are enveloped—their virions contain an outer lipid bilayer originating from a host cell. Small molecule antivirals targeting the lipid bilayer cover the broadest spectrum of viruses. In this context, we consider the chemical nature and mechanisms of action of membrane-targeting antivirals. They can affect virions by (1) physically modulating membrane properties to inhibit fusion of the viral envelope with the cell membrane, (2) physically affecting envelope lipids and proteins leading to membrane damage, pore formation and lysis, (3) causing photochemical damage of unsaturated membrane lipids resulting in integrity loss and fusion arrest. Other membrane-active compounds can target host cell membranes involved in virion’s maturation, coating, and egress (endoplasmic reticulum, Golgi apparatus, and outer membrane) affecting these last stages of viral reproduction. Both virion- and host-targeting membrane-active molecules are promising concepts for broad-spectrum antivirals. A panel of approved antivirals would be a superior weapon to respond to and control emerging disease outbreaks caused by new viral strains and variants.

The development of broad-spectrum antiviral drugs effective against a wide variety of viruses is of significant practical importance. Perylene derivatives, which are pentacyclic aromatic hydrocarbons, have demonstrated strong antiviral activity. These compounds primarily act as membranoactive singlet oxygen photogenerators, disrupting virions and inhibiting fusion in enveloped viruses. Modifying the perylene core allows for chemical diversification of antiviral photosensitizers. Additionally, achieving a bathochromic shift in absorbance is crucial for the effective treatment of superficial lesions, as it facilitates deeper tissue penetration of therapeutic light. In this work, donor–acceptor perylenylethylenes and (perylenethienyl)ethylenes were synthesized and evaluated for their spectral properties, singlet oxygen photogeneration, and antiviral activity against vesicular stomatitis virus (VSV), a representative enveloped virus. The incorporation of a thiophene unit into the molecule significantly enhanced both the quantum yield of singlet oxygen generation and the antiviral activity. These findings provide valuable insights into the relationship between the structure, spectral/photochemical properties, and biological activity of perylene-based photosensitizers.