Hybrid Design of Amino Acid-Derived 2-(2-(Phenoxymethyl)-1H-benzimidazole Analogues: Synthesis, In Silico Profiling, and Evaluation of Anxiolytic Potential

Benzimidazoles represent an important class of heterocycle compounds that are established with diverse pharmacological potential, including significant anxiolytics, which are effective in the treatment of anxiety disorders. Motivated by this therapeutic relevance, the objective of this research is to incorporate the synthesis of amino-acid derived newer benzimidazole derivatives substituted with heterocyclic and aromatic ring systems, focusing on their anxiolytic action. Amino acid-derived 2-(2-(phenoxymethyl)-1H-benzo[d]imidazol-1-yl) analogues (6a–g) were synthesized with rapid and efficient methods, yielding good results. Derivatives were analyzed using IR, NMR (1H NMR and 13C NMR), and mass spectroscopy, and drug-likeness suggesting in silico ADME and toxicity profiling using SwissADME and Protox 3.0. All derivatives (6a–g) followed Lipinski’s rule of five and were predicted to have no toxicity. Additionally, molecular docking of these synthesized compounds demonstrated that these derivatives block 6VRH receptors using the same mechanism as diazepam. The compounds 6a, 6d, 6f, and 6g demonstrated substantial binding affinities along with significant interaction with active site residues against 6VRH. In vivo anti-anxiety potential evaluation of these newly synthesized compounds shows a positive response in Swiss albino mice. The synthesized compounds exhibited promising anxiolytic potential, where these derivatives 6a, 6d, 6f, and 6g were found to be the most active lead candidates.