Medicinal Chemistry Research https://doi.org/10.1007/s00044-018-2141-9 MEDICINAL CHEMISTR Y RESEARCH ORIGINAL RESEARCH Design, synthesis, evaluation and molecular modeling studies of some novel N-substituted piperidine-3-carboxylic acid derivatives as potential anticonvulsants Ankit Seth 1 ● Piyoosh A. Sharma 1 ● Avanish Tripathi 1 ● Priyanka K. Choubey 1 ● Pavan Srivastava 1 ● Prabhash Nath Tripathi 1 ● Sushant Kumar Shrivastava 1 Received: 25 September 2017 / Accepted: 20 January 2018 © Springer Science+Business Media, LLC, part of Springer Nature 2018 Abstract Novel Schiff bases of 1-(2-Aminoethyl)piperidine-3-carboxylic acid were synthesized, characterized and screened for anticonvulsant activity. Compounds were evaluated for in vitro blood–brain barrier (BBB) permeability by parallel artificial membrane permeability BBB assay (PAMPA-BBB). Compounds 5d, 5f, 5j, 5l, 5m, 5n, 5w, 5x and 5y elicited considerable in vitro permeability across BBB and further screened for in vivo anticonvulsant activity by sc-PTZ and DMCM-induced seizure models. The outcome of the in vivo models suggested that 5d, 5w, and 5y were most potent amongst the synthesized compounds. The neurotoxicity evaluation of 5d, 5w, and 5y by rotarod indicates no impairment of muscle coordination in comparison to standard diazepam. The MTT assay revealed that the test compounds (5d, 5w, and 5y) were not found to alter the cell viability considerably. In silico molecular docking and dynamics simulations were carried out on the homology modeled protein of human GABA transporter 1 (GAT1), which exhibited complementary interactions of compound 5w within the active binding pocket. Keywords Schiff bases ● Anti-convulsant ● Piperidine-3-carboxylic acid ● PAMPA-BBB ● Rota rod test ● MTT assay Introduction Epilepsy is a complex set of neurological disorders (Villalba et al. 2016), which is mainly characterized by unpredictable and frequent disturbances of normal brain function in the form of convulsive seizure episodes and/or loss of con- sciousness (Siddiqui et al. 2017). Despite the availability of numerous antiepileptic agents in the drug market, nearly 20–30% of the 70 million epilepsy patients worldwide have insufficient control over seizures and are resistant to the currently available pharmacotherapy (Ghareb et al. 2017). Moreover, the poor tolerability and reported side effects of the antiepileptic drugs have affected the quality of life of the epilepsy patients (El-Helby et al. 2017). Thus, to address these massive challenges, development of novel anti- epileptic drugs with improved efficacy, considerable toler- ability, and lower toxicity is a paramount necessity. GABA is the main inhibitory neurotransmitter in the brain of mammals that plays a considerable role in the pathogenesis of epilepsy (Holmes 1995). Low brain GABA concentration and diminution in GABA-ergic neuro- transmission have been observed in a range of epileptic syndromes (Petroff et al. 1996). The transport of GABA from synaptic cleft to the glial cells as well as presynaptic neurons is mediated by GABA transporters (GATs), which results in the termination of GABA-ergic neurotransmis- sion. GATs are the member of sodium symporters, which belong to solute carrier 6 (SLC6) transporter gene family in humans that mediates neurotransmitter transport (Chen et al. 2004). Elevation in GABA concentration within the synaptic cleft is proved to be advantageous in the man- agement of epilepsy. One such strategy for the up- regulation of GABA would be the blockade of specific * Sushant Kumar Shrivastava skshrivastava.phe@iitbhu.ac.in 1 Pharmaceutical Chemistry Research Laboratory, Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi 221005, India Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00044-018-2141-9) contains supplementary material, which is available to authorized users. 1234567890();,: