Background: Anxiety disorders are mental health conditions with a feeling of worry or fear, Current medication available in the market has suboptimal efficiency and tolerability which highlights the need for developing new drug treatments (Beck et al., 1988). The 4-Hydroxylphenylacetic acid (4-HPAA) is a natural compound found in biological sources. The 4-HPAA level has been linked to psychological disorders such as anxiety and depression (Sandler et al., 1979). The previous pharmacokinetic studies demonstrated 4-HPAA has suboptimal pharmacokinetic including rapid elimination and difficulty in absorption (Zabela et al., 2016a). Methods: In this study synthesis of 4-HPAA derivatives such as Isopropyl 4-Hydroxyphenyl acetate (IHPA), Isopropyl 4-Methoxyphenyl acetate (IMPA), and 4-Methoxyphenylacetic acid (4-MPAA) and evaluation anxiolytic activity by Elevated plus-maze test (EPM), Elevated zero maze test (EZM), and locomotor activity by Actophotometer test in mice. Results: These efforts are indicative of 4-HPAA not being considered as an anxiolytic compound. Isopropyl (4-Hydroxyphenyl) acetate and Isopropyl (4-Methoxyphenyl) acetate may suggest anxiolytic properties. Conclusion: In this study Isopropyl 4-Hydroxyphenyl acetate and Isopropyl 4-Methoxyphenyl acetate are possible prodrugs that undergo metabolic activation before becoming physiologically active. Our hypothesis 4-HPPA convert to lipophilic prodrug to improved permeability through the blood-brain barrie for enhancing anxiolytic effect.