Vladislav S. Denisov

A series of hemicyanine derivatives was synthesized via condensation of 1,2,3,3‐tetramethyl‐3H‐indolium and its 5‐iodo and 4,6‐diiodo derivatives with polyaromatic aldehydes. Their spectral properties, singlet oxygen photogeneration, and inhibitory activity against vesicular stomatitis virus (VSV) were investigated. The aim of this study was to combine a positive charge for improved solubility with either a pyrene or perylene polycycle and heavy iodine atoms to enhance singlet oxygen generation and induce a bathochromic shift in the dye absorption. It was found that the synthesized hemicyanines are unstable both toward various nucleophiles, particularly the cyanide anion, and toward light. Although the perylene‐based derivatives demonstrate antiviral activity against VSV, the potential application of such compounds lies not in the antiviral domain but rather in the field of chemical sensors and pH indicators.

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 range of viruses is of significant practical importance. Derivatives of perylene, a pentacyclic aromatic hydrocarbon, demonstrate pronounced antiviral activity. These compounds act primarily as membrane‐active singlet oxygen photogenerators, disrupting virions and inhibiting their fusion with the host cell membrane. Modification of the perylene core allows for chemical diversification of antiviral photosensitizers. Additionally, achieving a bathochromic shift of the absorption band is crucial for 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 inhibitory activity against vesicular stomatitis virus (VSV), a representative enveloped virus. Incorporation of a thiophene moiety into the molecule significantly enhanced both the singlet oxygen generation ability and the antiviral activity. These findings provide useful insights into the relationship between the structure, spectral/photochemical properties, and biological activity of perylene‐based photosensitizers.

Enveloped viruses, such as flaviviruses and coronaviruses, are pathogens of significant medical concern that cause severe infections in humans. Some photosensitizers are known to possess virucidal activity against enveloped viruses, targeting their lipid bilayer. Here we report a series of halogenated difluoroboron-dipyrromethene (BODIPYs) photosensitizers with strong virus-inactivating activity. Our structure-activity relationship analysis revealed that BODIPY scaffolds with a heavy halogen atom demonstrate significant efficacy against both tick-borne encephalitis virus (TBEV; Flaviviridae family) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; Coronaviridae family) along with high singlet oxygen quantum yields. Moreover, select compounds also inactivated other enveloped viruses, such as herpes simplex virus type 1 and monkeypox virus. The nature and length of the alkyl side chain notably influenced the virus-inactivating activity of BODIPY molecules. Furthermore, molecular dynamics studies highlighted the critical importance of the positioning of the chromophore moiety within the lipid bilayer. As membrane-targeting photosensitizers, BODIPYs interact directly with virus particles, causing damage to the viral envelope membranes. Thus, TBEV pretreated with BODIPY was completely noninfective for lab mice. Consequently, BODIPY-based photosensitizers hold potential either as broad-spectrum virus-inactivating antivirals against a variety of phylogenetically unrelated enveloped viruses or as potent inactivators of viruses for the development of vaccines for preventing life-threatening emerging viral diseases.

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.