Design, in silico study, and efficient synthesis of N-acylhydrazones in deep eutectic solvents: potential...

In medicinal chemistry, the search for effective epilepsy treatments remains critical, as current drugs often show limited efficacy, require combinations, and cause adverse effects. This work aims to synthesize N-acylhydrazones derived from isatin and to explore approaches that combine sustainable organic synthesis methodologies and advanced computational tools for the identification and development of novel antiepileptic drug candidates. The present methods consisted of the synthesis of N-acylhydrazones using a deep eutectic solvent (DES) composed of choline chloride and p-toluene sulfonic acid (p-TSA), which enabled the development of an efficient, selective, and environmentally friendly synthetic route. Eighteen isatin derivatives were synthesized in a few minutes with good to excellent product yields, and the low solubility of some substrates was overcome by moderate heating. DES demonstrated high recyclability, being reused for up to four cycles without any loss of activity. Additionally, in silico analyses were performed to evaluate the ligand-receptor interactions between the compounds and the GABA_A receptor, a key therapeutic target for modulating epileptic seizures. The synthesized compounds exhibit favorable interactions within the GABA_A receptor binding site, including hydrogen bonds, hydrophobic contacts, and aromatic stacking interactions. Compounds 3d, 3e, and 3o are noteworthy for interacting with key residues associated with biological activity, showing promising binding profiles compared to reference ligands. This study reinforces the potential of DES and virtual screening as modern and effective approaches in the development of antiepileptic drugs.