Design, synthesis and anticonvulsant evaluation of novel 2,4,5-trichlorobenzenesulfonate-based dihydrothiazoles supported by in vivo and in silico studies

Abstract

This study describes the synthesis of a new series of 2,4,5 trichlorobenzenesulfonate structural class dihydrothiazoles and assesses the potential of the compounds as antiepileptic drugs using in vivo methods, network pharmacology, molecular docking, and DFT computational methods. Ten compounds 3(a–j) were synthesized and characterized, and their anti-seizure effects were evaluated on the standard seizure models. In vivo anticonvulsant activity was explored in the 6 HZ corneal stimulation model. Compound 3c showed complete protection, with return to normal behavior in less than 10 seconds post stimulation. The rest of the compounds exhibited 25% (3a), 50% (3d), 75% (3f), and 75% (3j) protection, respectively. In the pentylenetetrazole (PTZ) chemoconvulsant model, compound 3c at 150 mg kg⁻¹ showed complete protection from death and hind limb extension. None of the animals showed seizure activity for 30 minutes post-administration. In the in silico molecular docking, compound 3c showed the greatest anticonvulsant activity among the synthesized compounds. Compound 3c had a binding affinity of −9.7 kcal mol⁻¹, while the co-crystallized reference ligand had −6.7 kcal mol⁻¹ which indicates a direct correlation between binding score and experimental anticonvulsant activity. Based on both in vivo and in silico findings, compound 3c emerged as the most important candidate, demonstrating superior anti convulsant activity across multiple seizure models. These results underscore the capability of the newly synthesized 2, 4, 5-trichlorobenzenesulfonate based dihydrothiazoles as promising scaffolds for the development of new antiepileptic drugs.