Gallopamil exhibits antiplasmodial activity against Plasmodium falciparum and Plasmodium vivax and shows predicted interactions with Plasmodium hexose transporters.

Malaria remains a major parasitic disease caused mainly by Plasmodium falciparum and Plasmodium vivax, and drug-resistant parasites continue to challenge disease control. Drug repurposing may help identify compounds with antimalarial potential. Here, we evaluated gallopamil, an L-type calcium channel blocker, using in vitro, ex vivo, in vivo and in silico approaches. Gallopamil inhibited the chloroquine-resistant P. falciparum W2 strain in vitro (IC₅₀ = 3.65 µM) and showed ex vivo activity against clinical isolates of P. falciparum and P. vivax from CEPEM/RO, with median IC₅₀ values of 6.4 and 9.87 µM, respectively. Selectivity indices calculated using HepG2 cytotoxicity data ranged from >51 to >137, indicating in vitro selectivity relative to HepG2 cells. In a preliminary murine P. berghei suppressive assay, gallopamil at 5 mg/kg reduced parasitemia by more than 40% at the day-5 endpoint, as measured by light microscopy and flow cytometry. Stage-specific assays showed that gallopamil inhibited parasite development when treatment began at the ring stage (p < 0.000001), whereas no significant inhibition was observed when treatment started with predominantly schizont-stage parasites (p = 0.30). Molecular docking predicted interactions between gallopamil and residues of Plasmodium hexose transporters, including LYS-51, GLN-167, ASN-309 and ASN-339, with binding energies of -6.1 kcal/mol for PvHT1 and -7.8 kcal/mol for PfHT1. These findings support gallopamil as an early antiplasmodial hit compound and provide a transporter-related mechanistic hypothesis for future functional validation.