Synthesis and Evaluation of Novel Synthetic Piperazine Derivatives with Biological and Anxiolytic Potency: A Preliminary Report

Abstract

Anxiety is one of the mental conditions that has a substantial impact on individual health and well-being and is a major issue of concern in societies globally. Stress and anxiety are neurological syndromes affecting humans and animals. Current treatment regimens for anxiety disorders include benzodiazepines, antidepressants (like SSRIs and SNRIs), and beta-blockers. Each of these drugs has its advantages and drawbacks. To this end, in recent years, the pharmacological properties of many synthetic heterocyclic compounds have proven to possess higher biological efficacy in the treatment of several CNS (central nervous system) disorders. With this background, the aim of the present research was to design and study cellular and anxiolytic effects of novel synthetic piperazine derivative compounds. We have synthesized 5 novel derivatives of piperazine (PD1-PD5). The results of the cellular assays are as follows: in the microbial assay the compound PD2 demonstrated an inhibition zone of 1.3 cm and MIC value to be 0.2±0.24 mg/ml. Whereas, the antioxidant activity of compounds was as follows: PD5 toxicity had a range of 53.60% - 78.04% (DPPH assay), and compound PD2 had 64.15% - 77.26% (H₂O₂ scavenging) toxicity. In the cytotoxic assays, PD3 compound demonstrated higher viability at 56.81% (trypan blue test) and PD2 64.39% viability (resazurin test). Behavioral assays indicated increased traveled distance and locomotion activity at low (2.5 µg/ml) and high (5.0 µg/ml) doses in comparison to the control group. PD2-treated fish showed anti-anxiety activity and spent more time in the green zone. Finally, caffeine-treated fish spent more time in the dark zone, implying anxiety, whereas piperazine derivative-treated fish spent more time in the light zone, implicating reduced anxiety. In summary, the present study demonstrates the hybrid role of compound PD2 with anti-microbial, cytotoxic, and anti-oxidant properties. Also, it reestablishes zebrafish as a model for behavioral studies.