Novel Benzimidazole Linked Isoxazoline Derivatives: Molecular Docking, Synthesis, and Pharmacological Evaluation for Anti-Ulcer and Anti-Histaminic Activities

Gastric acid and pepsin damage the GI tract lining in peptic ulcer disease. It affects many people worldwide, especially in developing countries. H1 antihistamines relieve allergy symptoms by blocking H1 receptors, which histamine binds. We designed novel benzimidazole-linked isoxazoline derivatives, molecular docking was carried out to study their possible target interaction with the anti-ulcer associated target 7W48 and H1 antihistaminic target 8X5Y, and synthesized 1-hydroxyethyl)-1H-benzimidazole by condensation of o-phenylenediamine with lactic acid. Claisen-Schmidt condensation of ketone derivatives with substituted aromatic aldehydes produced chalcones. Benzimidazole-linked isoxazoline derivatives (6a-6h) were produced by hydroxylamine hydrochloride cyclization. The ligands with the highest docking scores were selected for biological target evaluation (6d: -7.66 and 6e: -8.62, respectively). In ethanol-induced gastric ulcer models, compound 6d showed dose-dependent gastroprotection, with ulcer indices of 4.227 ± 0.110 (200 mg/kg) and 3.523 ± 0.095 (400 mg/kg) exhibiting 27.59% and 39.64% inhibition, respectively, but less effective than omeprazole (1.380 ± 0.046; 76.36% In an ex vivo study, compound 6e showed concentration-dependent inhibition (20.700 ± 0.990%-73.800 ± 0.849% at 200-400 mg/kg), but less than Mizolastine (80.700 ± 0.849% at 1.6 μg/ml). Compound 6d had dose-dependent antiulcer activity. The concentration-dependent anti-histaminic activity of compound 6e was significant. Standard drugs (omeprazole and mizolastine) were stronger than both compounds. These derivatives showed promising gastroprotective and antihistaminic properties and can be used as lead for further optimization and development. The combined molecular docking and biological evaluation results suggest that compounds 6d and 6e can be further explored for anti-ulcer and antihistaminic activities, respectively. Nevertheless, to confirm their suitability for further drug development studies, experimental validation of their ADME-related properties, toxicity predictions, and proposed molecular mechanisms is required.