Molecular docking and In-Silico pharmacokinetic analysis of 1,3-benzothiazole-2-amine derivatives as anticonvulsants

Derivatives bearing thiazole groups are very important pharmacophores in medicinal chemistry due to their broad pharmacological properties. Benzothiazole is an important scaffold with a range of biological activities and therapeutic uses, including antibacterial, antimalarial, anticonvulsant, analgesic, anti-inflammatory, antidiabetic, and anticancer properties. In this study, we evaluated the in-silico pharmacokinetic features of 15 derivatives of 1,3-benzothiazole-2-amine (analogues) and their interactions with two critical epilepsy targets: γ-aminobutyric acid-aminotransferase (GABA-AT) and activated open sodium ion channel (NavMs) proteins.

The chemical structures of the derivatives were designed and optimized using MarvinSketch and Spartan software. In-silico pharmacokinetic features were studied using the SwissADME server. Molecular docking was conducted with Autodock Vina, Chimera, and Discovery Studio Visualizer.

Four analogues (2, 5, 6, and 7) failed the blood-brain barrier (BBB) penetration test, but 11 of the 15 analogues had good pharmacokinetic characteristics. The validation results showed that the procedure employed was suitable for molecular docking analysis of the test analogues in the active sites of the two target proteins. Compared with the reference medication vigabatrin (-5.2 kcal/mol), seven analogues (A₁, A₃, A₉, A₁₀, A₁₁, A₁₂, and A₁₄) had higher binding affinities (-5.9, -5.8, -6.1, -5.9, -6.0, -6.1, and -6.6 kcal/mol, respectively) for GABA-AT binding. NavMs binding analysis showed that only analogue A₁₄ had a binding affinity (5.0 kcal/mol) comparable to that of the reference medication lamotrigine.

In-silico investigations identified benzothiazole compounds with high anticonvulsant properties as suitable candidates for synthesis and pharmacological testing.