Targeting voltage-gated proton channel H$_V$1 : optimised 5-phenyl-2-aminoimidazoles with anticancer potential

Piga, Martina (author), Domingos, Geraldo Jorge (author), Fehér, Ádám (author), Papp, Ferenc (author), Bangera, Kavya C. (author), Varga, Zoltán (author), Zakany, Florina (author), Kovacs, Tamas (author), Dernovšek, Jaka (author), Tomašič, Tihomir (author), Zidar, Nace (author)

The voltage-gated proton channel (H$_V$1) has been linked to the development of tumours, neuroinflammatory diseases, immune disorders and infertility, making H$_V$1 inhibitors promising candidates for therapeutic development. In this study, we designed and synthesized an optimised series of 5-phenyl-2-aminoimidazole-based H$_V$1 inhibitors, with the most potent compounds exhibiting low micromolar IC$_{50}$ values. Structural analysis highlighted the importance of an unsubstituted 2-aminoimidazole core and flexible linkers for optimal ligand-channel binding, driven by hydrogen bonding and hydrophobic interactions. Antiproliferative assays showed that the most potent H$_V$1 inhibitors had IC$_{50}$ values in the low micromolar range, with greater efficacy against THP-1 cells (human monocytic leukaemia), which express H$_V$1 at high levels, compared to MCF-7 cells (human breast cancer) with lower H$_V$1 expression. The type II compounds exhibited superior drug-like properties, including improved solubility, plasma protein binding and permeability compared to previous 5-phenyl-2-aminoimidazole-based H$_V$1 inhibitors, as well as robust metabolic stability. However, selectivity over the K$_V$1.3 and Na$_V$1.5 channels remained limited. This work advances the development of H$_V$1 inhibitors. It provides valuable chemical tools to study the role of HV1 in disease pathogenesis and lays the foundation for new therapeutic strategies targeting H$_V$1-mediated signalling pathways.

• Language: English
• Keywords: anticancer, H$_V$1, inhibitor, 5-phenyl-2-aminoimidazole, voltage-gated proton channel
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2025
• Number of pages: 25 str.
• Numbering: Vol. 297, art. 117936
• PID: 20.500.12556/RUL-181042
• UDC: 615.4:54
• ISSN on article: 1768-3254
• DOI: 10.1016/j.ejmech.2025.117936
• COBISS.SI-ID: 243284227
• Publication date in RUL: 23.03.2026

Record is a part of a journal

• Title: European journal of medicinal chemistry
• Shortened title: Eur. j. med. chem.
• Publisher: Elsevier
• ISSN: 1768-3254
• COBISS.SI-ID: 23138309

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: zaviralci, HV1, 5-fenil-2-aminoimidazol, napetostno odvisen protonski kanal, rak, medicina, farmacevtska kemija