Thiazol-4-yl-Methylthio-Quinazolin-4(3H)-ones as Anticonvulsant Compounds: Chemical Design, Computational Studies,...

The purpose of this study was the chemical design, synthesis, and evaluation of the anticonvulsant potential of 15 novel thiazolyl-methylthio-quinazolin-4(3H)-one hybrid compounds (4a-o). The compounds were designed based on a scaffold that reunited thiazole and quinazolin-4(3H)-one heterocycles of two well-known anticonvulsants, clomethiazole and methaqualone, through a condensation reaction. The compounds were evaluated in vivo for anticonvulsant activity using the pentylenetetrazole-induced seizure animal model. A Rotarod test was employed to evaluate the neuromotor coordination after the administration of the tested compounds, and a flumazenil antagonism assay was subsequently performed to investigate if the observed anticonvulsant effects were mediated through the compounds' interaction with the GABA_A receptor. The in silico assessment consisted of molecular docking, evaluation of the druggability, and ADMETox prediction. All compounds presented anticonvulsant activity to varying degrees. The most notable activity was observed in compounds 4k (ED₅₀ = 84.313 mg/kg) and 4c (ED₅₀ = 178.165 mg/kg). The in vivo results positively correlated with the observations drawn in the molecular docking study on the human α₁β₂γ₂ GABA_A receptor and on the NR1 ligand-binding core of the NMDA receptor. The potential of anticonvulsant activity was also supported by the druggability and ADMETox predictions that highlighted an increased possibility of brain-blood barrier permeation, supported by the computed parameters TPSA, logD, and logBB. The results of the flumazenil antagonism assay additionally highlighted the possible mechanism of action of compounds 4c and 4k as positive allosteric modulators of the GABA_A receptor. Preliminary evaluation confirmed the anticonvulsant potential of the tested compounds, with further testing being necessary for a better understanding and confirmation of the activity.