Neurotropic potential and docking investigations of newly synthesized triazolopyridine and triazolothienopyridine derivatives.

A series of novel tricyclic and tetracyclic S-alkyl derivatives based on fused triazolopyridine and thienotriazolopyridine scaffolds were synthesized and evaluated for potential neuroactive properties. The compounds were obtained through optimized alkylation and intramolecular cyclization procedures, yielding the target heterocycles in high purity. Their anticonvulsant, anxiolytic and antidepressant activities were assessed using pentylenetetrazole (PTZ) induced seizure, tonic seizure threshold, open-field, elevated plus maze (EPM) and forced swim (FS) models. Ten derivatives demonstrated marked anticonvulsant activity in the PTZ model, with ED50 values lower than that of ethosuximide under the present experimental conditions. Within the tested series, compound 2g showed the highest activity without inducing muscle relaxation. Compound 3f demonstrated notable anxiolytic effects. Compounds 3e and 3f significantly reduced immobility time in the FS test, indicating antidepressant-like activity. Molecular docking studies suggested that triazolopyridine derivatives (2a, 2b, 2g, 2h, 2i) may interact with GABAA, SERT and 5-HT1A receptors, whereas thienotriazolopyridine analogues appear to preferentially target serotonergic systems, supporting a possible multitarget mechanism of action. Compound 2g showed the strongest GABAA binding affinity (ΔG = -8.42 kcal mol-1), and 3f exhibited the highest affinity for SERT (ΔG = -10.45 kcal mol-1). These findings highlight the potential of fused triazolopyridine-based heterocycles as promising lead structures for the development of novel neuroactive agents with combined anticonvulsant and psychotropic properties.