Synthesis and Evaluation of Benzimodazole Derivatives in Haloperidol Induced Hyperprolactenemia

ABSTRACTHyperprolactinemia is a common adverse effect of chronic neuroleptic (antipsychotic) therapy, causing endocrine and reproductive dysfunction. We report here the synthesis of novel benzimidazole derivatives and their ability to suppress prolactin in a rat model of haloperidol-induced hyperprolactinemia. Two compounds (a salicylate-derived benzimidazole and its phenyl analogue) were prepared via acid-catalysed condensation of o-phenylenediamine with salicylic or benzoic acid, and fully characterised by melting point, IR, NMR, and mass spectrometry (see Methods). In Sprague Dawley rats, daily haloperidol (1 mg/kg) produced significant hyperprolactinemia (9.23±0.08 ng/mL, vs. 1.01±0.03 ng/mL in controls). Co-administration of cabergoline (0.6 mg/kg) or the synthesised benzimidazole significantly reversed this effect. Notably, Compound 1 (2-(1H-benzimidazol-2-yl)phenol) at 100–200 mg/kg normalised prolactin to near-baseline (e.g., 0.04±0.20 ng/mL in males), matching or exceeding the efficacy of cabergoline (0.62±0.01 ng/mL in males). The test compounds also restored antioxidant defences (superoxide dismutase and catalase) that were disrupted by haloperidol, and protected hippocampal neurons from degeneration. These data demonstrate that the novel benzimidazole derivative is a potent prolactin-inhibiting agent in this model. By acting analogously to dopamine agonists, it represents a promising lead for treating antipsychotic-induced hyperprolactinemia.