Epilepsy is a chronic neurological disorder affecting many people worldwide, however, the low efficacy and the adverse side effects as well as the resistance of many patients to the available antiepileptic drugs have encouraged the persistent endeavor in the discovery of new effective antiepileptic medications. Considering the preceding researches that asserted the efficacy of pyrimidine-based compounds as anticonvulsant agents, the present investigation focused on the synthesis of new substituted thiopyrimidine derivatives in addition to the incorporation of the pyrimidine scaffold with different substituted hydrazinyl moieties and various heterocyclic rings 2-14 to evaluate their anticonvulsant effect utilizing pentylenetetrazole (PTZ) and Maximal electroshock (MES) tests. Derivatives 8b, 8c, 8d, 10b and 11 displayed remarkable anticonvulsant efficiency relative to Phenytoin and Carbamazepine as reference drugs. Moreover, the latter derivatives were subjected to further neurochemical studies to determine their effects on various neurotransmitters in the brain such as GABA, norepinephrine, dopamine, serotonin, and glutamate. They displayed a notable elevation of GABA, norepinephrine, dopamine, and serotonin levels (GABA level range 2.62-3.86 µg/g tissue, norepinephrine level range 0.53-0.85 µg/g tissue, dopamine level range 1.80-2.63 µg/g tissue, serotonin level range 0.50-0.73 µg/g tissue) compared to Carbamazepine (3.80, 0.88, 2.85 and 0.82 µg/g tissue, respectively). Otherwise, the investigated candidates effectively reduced the glutamate levels ranging between 3.67-5.70 µg/g tissue comparing to carbamazepine (2.65 µg/g tissue). In silico ADMET prediction results revealed that the most potent pyrimidine candidates have good physicochemical and pharmacokinetic properties. Also, the binding interactions of the most prominent candidates within the active sites of GABA-AT enzyme and GluA2 subtype AMPA receptor were illustrated by carrying out a docking study.