Investigation of Indole‐3‐piperazinyl Derivatives as Potential Antidepressants: Design, Synthesis, In‐Vitro, In‐Vivo and In‐Silico Analysis

Abstract

Depression is declared the second leading cause of disability worldwide. Recently, cases of depression have increased significantly in adolescents, young adults as well as in elder population. Monoamine oxidase‐A (MAO‐A) is considered one of the major targets for the treatment of depression. In the current study, we have designed and synthesized various indole functionalized piperazinyl derivatives and evaluated them for in vitro MAO‐A inhibitory activity and in vivo antidepressant‐like activity. Most of the compounds were found to possess potent MAO‐A inhibitory activity with IC50 values in the sub‐micromolar range along with significant selectivity over MAO‐B. Compounds RP1 and RP9 emerged as the most promising reversible MAO‐A inhibitors with IC50 values of 0.11±0.03 μM and 0.14±0.02 μM and displayed selectivity of 193 folds and 178 folds over Monoamine oxidase‐B (MAO‐B), respectively. In the series, RP1 showed good intracellular ROS inhibitory activity along with neuroprotective properties. These compounds were found nontoxic against SH‐SY5Y cells and explored antidepressant activities. In the in vivo Forced swimming test (FST) and Tail suspension test (TST) studies, RP1 exhibited potential antidepressant‐like behavior similar to standard drug fluoxetine while compound RP9 showed antidepressant‐like activity only in the TST studies. The molecular docking and dynamics studies further supported the results obtained in the in vitro and in vivo studies. Thus, the indole functionalized piperazinyl derivatives were found to be promising ligands and can be developed as new antidepressant molecules.

Rationale Design, Synthesis, Pharmacological and In‐silico Investigation of Indole‐Functionalized Isoxazoles as Anti‐inflammatory Agents

“…Drug likeliness properties of the synthesized compounds were predicted using Swiss ADME predictor. [19] The synthesized molecules revealed good absorption in the range of 86-98 %. Obtained results evidenced that the compounds showed no violation of Lipinski's Rule of Five as represented in Table 6.…”

“…These properties are important to predict the bioavailability of drugs and medicinal chemist can modify the factors affecting it accordingly. Drug likeliness properties of the synthesized compounds were predicted using Swiss ADME predictor [19] . The synthesized molecules revealed good absorption in the range of 86–98 %.…”

Imidazoles as Serotonin Receptor Modulators for Treatment of Depression: Structural Insights and Structure–Activity Relationship Studies

“…Arylpiperazine-substituted imidazole derivatives are one of the major classes explored in various neurological disorders [ 118 , 119 , 120 ]. Zagόrska et al synthesized a novel series of arylpiperazinylalkyl purine-2,4-diones ( 4a – u ) and purine-2,4,8-triones ( 5a – h ) and screened them in vitro for their serotonergic and dopaminergic receptor affinity.…”

Nitrogen‐containing heterocyclic compounds: A ray of hope in depression?

“…By including a 2%–6% margin error, 3.4% of the global population is suffering from depression (Park et al., 2022; World Health Organization, 2023). On average, around 3.8% population is affected by depression worldwide, which includes the adult population majorly and has aged more than 60 years (Kumar, Kumar, et al., 2021; Verdeş, 2022; World Health Organization, 2023). So, approximately 280 million people are suffering from depression worldwide which means that it is not a passing problem but a continuing problem (Alvano & Zieher, 2020).…”