Exploring quinoline tethered N-acetylated-1,3,4-oxadiazole hybrids as a promising anxiolytic agent: Synthesis, in vivo biological and in Silico studies

Abstract

A series of fifteen quinoline-linked N-acetylated 1,3,4-oxadiazole derivatives (4a–4o) were synthesized and structurally characterized using ¹H NMR , ¹³C NMR , and mass spectrometry. Their in vivo anxiolytic potential was evaluated using the elevated plus maze (EPM) model in mice. Compounds 4d and 4h exhibited significant anxiolytic activity, with compound 4h demonstrating a time spent in open arms of 160.2 ± 2.48 s, which was comparable to that of the standard drug diazepam (154.5 ± 3.77 s). Structure-activity relationship (SAR) analysis indicated that electron-donating substituents and the oxadiazole scaffold contributed positively to biological activity. Molecular docking studies revealed favourable interactions between these compounds and GABA receptor sites, supporting their mechanism of action. In silico ADME and toxicity assessments using SwissADME and ProTox-II (v3.0) predicted good oral bioavailability, drug-likeness, and low toxicity. In addition, Density Functional Theory (DFT) studies were carried out on lead compound (4h) demonstrated the FMO energy of difference (ΔE) of 7.67 eV and electronic distribution was depicted by computing Molecular Electrostatic Potential (MEP) map. These findings suggest that oxadiazole derivatives, particularly compound 4h, may serve as promising biological lead for the development of new anxiolytic agents.