20.500.12556/RUL-181042 Targeting voltage-gated proton channel H$_V$1 optimised 5-phenyl-2-aminoimidazoles with anticancer potential The voltage-gated proton channel (H$_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$1-mediated signalling pathways. anticancer H$_V$1 inhibitor 5-phenyl-2-aminoimidazole voltage-gated proton channel zaviralci HV1 5-fenil-2-aminoimidazol napetostno odvisen protonski kanal rak medicina farmacevtska kemija true false true Angleški jezik Slovenski jezik Članek v reviji 2026-03-23 16:01:09 2026-03-23 16:01:20 2026-03-24 04:26:39 0000-00-00 00:00:00 2025 0 0 25 str. art. 117936 Vol. 297 2025 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 615.4:54 1768-3254 10.1016/j.ejmech.2025.117936 243284227 1-s2.0-S0223523425007019-main.pdf 1-s2.0-S0223523425007019-main.pdf 1 F20E02513EB71EB9BC8F5618B8C893FE 46cc106240e361bf99a51ba2d5715dfff52bd8e17abd01f53625f5c325cba3e6 54c8b3a1-26c9-11f1-b0ab-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=231139 https://www.sciencedirect.com/science/article/pii/S0223523425007019 1 0aba0f07-26c9-11f1-b0ab-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=231138 Fakulteta za farmacijo 0 0 0