In silico Study of Potential Non-oxime Reactivator for Sarin-inhibited Human Acetylcholinesterase

The search for new compounds other than oxime as potential reactivator that is effective upon organophosphate poisoning treatments is desired. The less efficacy of oxime treatment has been the core factor. Fourteen compounds have been screened via in silico approach for their potential as sarin-inhibited human acetylcholinesterase poisoning antidotes. The selection of the compounds to be synthesized based on this computational screening, reduces the time and cost needed. To perform the docking study of sarin-inhibited acetylcholinesterase and reactivator-sarin inhibited acetylcholinesterase complexations, a bioinformatics tool was used. Estimation of the nucleophilic attack distance and binding energy of fourteen potential compounds with sarin inhibited acetylcholinesterase complexes to determine their antidote capacities was carried out using Autodock. A commercially available antidote, 2-PAM was used for the comparison. The best docked-pose was further examined with molecular dynamics simulation. Apart from being lipophilic, a compound with a carboxylic acid, (R)-Boc-nipecotic acid is shown to exhibit 6.29 kcal/mol binding energy with 8.778 Å distance of nucleophilic attack. The stability and flexibility of the sarin-inhibited acetylcholinesterase, complexed with (R)-Boc-nipecotic acid suggests this compound should be tested experimentally as a new, promising antidote for sarin-inhibited acetylcholinesterase poisoning.

Design, Synthesis and Enhanced BBB Penetration Studies of L-serine-Tethered Nipecotic Acid-Prodrug

Nipecotic acid is considered to be one of the most potent inhibitors of neuronal and glial-aminobutyric acid (GABA) uptake in vitro. Due to its hydrophilic nature, nipecotic acid does not readily cross the blood-brain barrier (BBB). Large neutral amino acids (LAT1)-knotted nipecotic acid prodrug was designed and synthesized with the aim to enhance the BBB permeation by the use of carrier-mediated transport. The synthesized prodrug was tested in animal models of Pentylenetetrazole (PTZ)-induced convulsions in mice. Further pain studies were carried out followed by neurotoxicity estimation by writhing and rota-rod test respectively. HPLC data suggests that the synthesized prodrug has improved penetration through BBB. Nipecotic acid-L-serine ester prodrug with considerable anti-epileptic activity, and the ability to permeate the BBB has been successfully synthesized. Graphical Abstract.

Synthesis and biological evaluation of novel N-substituted nipecotic acid derivatives with tricyclic cage structures in the lipophilic domain as GABA uptake inhibitors

A new class of GABA reuptake inhibitors with sterically demanding, highly rigid tricyclic cage structures as the lipophilic domain was synthesized and investigated in regard to their biological activity at the murine GABA transporters (mGAT1–mGAT4). The construction of these compounds, consisting of nipecotic acid, a symmetric tricyclic amine, and a plain hydrocarbon linker connecting the two subunits via their amino nitrogens, was accomplished via reductive amination of a nipecotic acid derivative with an N-alkyl substituent displaying a terminal aldehyde function with tricyclic secondary amines. The target compounds varied with regard to spacer length, the bridge size of one of the bridges, and the substituents of the tricyclic skeleton to study the impact of these changes on their potency. Among the tested compounds nipecotic acid ethyl ester derivates with phenyl residues attached to the cage subunit showed reasonable inhibitory potency and subtype selectivity in favor of mGAT3 and mGAT4, respectively.