Design, synthesis, in vivo, and in silico evaluation of novel quinoline-based dihydrothiazoles as anticonvulsants.

The current study reports the synthesis of a novel series of quinoline-based dihydrothiazoles compounds, 3(a-j), and evaluates their potential as antiepileptic agents. Chemical synthesis, NMR, and SAR showed important insights and correlation with structure and biological efficacy. The in vivo anticonvulsant activity was assessed using an acute chemoconvulsant model, where seizures were induced by a single dose of pentylenetetrazole (PTZ 80 mg/kg). Electroencephalographic (EEG) recordings of treated animals showed a substantial reduction in epileptic activity compared to the PTZ-only group, indicating the compounds' anti-ictal efficacy. In vivo, compounds 3d and 3i significantly delayed the onset of tonic-clonic seizures (591.7 ± 13.2 s and 556.3 ± 29.8 s, respectively, vs. 53.7 ± 4.3 s for PTZ alone; p < 0.0001) and conferred complete protection from PTZ-induced mortality. Molecular docking against the GABA-A receptor (PDB: 8G5G) predicted favorable binding energies for the series (best estimated score: -8.4 kcal/mol for 3 g), supporting a plausible GABAergic mechanism for the observed in vivo activity. The network pharmacology mapping, along with GO-enrichment analysis, highlighted the critical regulators in epilepsy treatment. Based on in vivo findings, compounds 3d and 3i emerged as the most potent candidates, demonstrating superior anticonvulsant activity in comparison with the standard reference drugs. Molecular docking against the GABA-A receptor additionally identified 3 g as the top computational binder, which is discussed as a complementary in silico finding along with experimentally validated lead.