A facile synthesis of 1,3,4-oxadiazole-based carbamothioate molecules: Antiseizure potential, EEG evaluation and in-silico docking studies
Abstract
In present work, a series of novel structural hybrids of 1,3,4-oxadiazole and carbamothioate was designed by chemical modification of 2-(4-isobutylphenyl)propanoic acid. Target compounds (7a-f) were synthesized in significant yields (84–88 %) by coupling compound (4) with different electrophiles under different reaction conditions. The structures of oxadiazole based carbamothionate derivatives were confirmed by spectroscopic (FTIR, 1H NMR, 13C NMR) and physiochemical methods. During in-vivo experimentation, all synthesized compounds were tested through 6 Hz (32 mA) and PTZ (80 mg/kg) mouse seizure models. The 7b and 7c showed significant outcomes (P < 0.05) in terms of seizure severity, protection and mortality. The behavioural outcomes of PTZ tests were further strengthened with video-electroencephalogram (vEEG) findings in which EEGs were analyzed for epileptic spikes to understand the impact of 7b and 7c treatment on these ictal activities. The 7b was found most efficient in reducing the seizure spiking activity in brains of PTZ-treated mice while both 7b and 7c significantly reduced overall PTZ-induced seizure severity. The molecular docking studies also predicted the BBB permeability, reduced binding energies and good compound interaction with GABAA receptors and SV2A protein. Therefore, the observed pharmacological outcomes might be attributed to the GABAA agonistic and SV2A modulating potential of these oxadiazole-carbamothioate hybrid compounds.
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