Objectives: In the current study, we report the synthesis, characterization and neuropharmacology of quinalozinones tethered with aromatic (3a- 3i) and heteroaromatic substitution (3j, 3k and 3l) as effective anxiolytic agents. Background: Anxiety and depression are often co-morbid with neurological as well as other medical maladies. Clinically popular anxiolytics (Benzodiazepines) are accompanied by untoward sedation and other CNS depressive actions. The quinazolinone moiety is a privileged pharmacophore with a wide pharmacological spectrum. we herein report the synthesis, characterization and pharmacological evaluation of some 2-substituted quinazolinone derivatives. Methods: The synthesized compounds were characterized using 1H-NMR and TLC analysis. Behavioral analysis was performed using EPM, OFT, PIST and FST bioassay. For further justifying the therapeutic claim, we performed systemic and neurotoxicological analysis of the most potent members of the series using OECD mandated protocols. The studies advocated the compounds to have a wide therapeutic window with >1000mg/kg and >500mg/kg LD50 and NOAEL respectively. Results: The compounds with an electronegative group in the quinazolinone nucleus (3f, 3e, 3d and 3c) induces anxiolysis devoid of sedative adverse reaction. In addition, Anti-depressant efficacy of 3f, 3e, 3d and 3c observed in rodents is a result of decrease in anxiety level. It has been found that Neurotoxicology of the potent members (3f, 3e, 3d and 3c) advocates their wide therapeutic window with >1000mg/kg LD50 and >5000mg/kg NOAEL. Conclusion: Our findings in behavioral bioassays reveal that inducing an electronegative group into the Quinazolinone nucleus yields the most potent members of the series (3f, 3e, 3d and 3c). The said compounds were found to render anxiolysis and anti-depressive action without sedative-hypnotic side effects in rodent models. In summary, we state that extending the studies in clinical setting would furbish the contours of current anxiolytic therapy especially in anxiety co morbid with medical maladies.