Synthesis and anticonvulsant screening of 1,2,4-triazole derivatives

Background

Currently available antiepileptic drugs offer limited symptomatic treatment and fail to cure more than 30% of the epileptic seizures. (Arylalkyl)azoles are a class of anticonvulsants including nafimidone and loreclezole. Here, we report the design and synthesis of new (arylalkyl)azoles in N-1-(4-chlorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethylidene]hydroxylamine ester structure, their anticonvulsant screening and in silico prediction studies of their pharmacokinetic properties.

Methods

The title compounds were synthesized according to the Steglich esterification of N-1-(4-chlorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethylidene]hydroxylamine with various carboxylic acids. Anticonvulsant identification and quantification tests were performed in mice by the Epilepsy Therapy Screening Program (ETSP) of the National Institutes of Health (NIH) using 6 Hz psychomotor, maximal electroshock (MES), and rotorod tests. Their physicochemical and pharmacokinetic properties were calculated using QikProp.

Results

Most of the compounds showed protection against 6 Hz- and/or MES-induced seizures. 4a, 4b, and 4 g were active at 100 mg/kg, 4 g was active in both tests without neurotoxicity. According to the QikProp calculations the title compounds were druglike and had some favourable properties such as high membrane permeability and oral absorptivity.

Conclusion

Anticonvulsant screening of a set N-1-(4-chlorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethylidene]hydroxylamine esters yielded some active derivatives in 6 Hz and MES test. Especially, 4 g emerged as a promising compound with activity at 100 mg/kg and no toxicity. The compounds were predicted to be drug like and have good pharmacokinetic properties except hERG inhibition, which needs to be addressed in further optimization studies.