Targeting voltage-gated proton channel H$_V$1Piga, Martina (Avtor) Domingos, Geraldo Jorge (Avtor) Fehér, Ádám (Avtor) Papp, Ferenc (Avtor) Bangera, Kavya C. (Avtor) Varga, Zoltán (Avtor) Zakany, Florina (Avtor) Kovacs, Tamas (Avtor) Dernovšek, Jaka (Avtor) Tomašič, Tihomir (Avtor) Zidar, Nace (Avtor) anticancerH$_V$1inhibitor5-phenyl-2-aminoimidazolevoltage-gated proton channelThe voltage-gated proton channel (H$_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.20252026-03-23 16:01:09Članek v reviji181042UDK: 615.4:54ISSN pri članku: 1768-3254DOI: 10.1016/j.ejmech.2025.117936COBISS_ID: 243284227sl