Design, Docking, Characterisation, and Synthesis of Pyrimidine Derivatives for Antidepressant Activity.

Background: According to the report, in 2022, the prevalence rate of depression in India was 4.50%, and the cases stood at 56,675,969. The development of antidepressant agents has reduced the number of depressant and suicidal cases. Many researchers have found that pyrimidine possesses antidepressant activity. With this background, we thought of synthesizing pyrimidine derivatives.

Objective: The objective of this study is to carry out molecular docking, synthesis, characterization, and evaluation of 2-((4,6-diphenylpyrimidin-2-yl)oxy)-N-phenylacetamide derivatives (17-26) as in vivo antidepressant agent.

Method: The designed compounds were checked for their activity using Molegro virtual docker (MVD) and were further synthesized. Benzaldehyde reacted with acetophenone to give compound (3), which gave compound (4) upon reaction with urea. In another reaction, substituted anilines (5) were reacted with chloroacetyl chloride (6) to yield compounds (7-16), which upon further reaction with compound (4) yielded the final derivatives (17-26). The synthesized compounds were characterized by spectral analysis and checked for their antidepressant activity.

Result: The MolDock scores of the derivatives ranged from -147.097 to -182.095, whereas of active ligand IXX_801 was -115.566. All the synthesized pyrimidine derivatives showed better affinity towards the Cryo-EM structure of the wild-type human serotonin transporter complexed with vilazodone, imipramine, and 15B8 Fab protein (PDB ID: 7LWD) as compared to standard drug clomipramine (-101.064). All the synthesized derivatives were screened for antidepressant activity at a 100mg/kg dose level compared to the standard clomipramine HCl at a dose level of 20mg/kg. Among all the synthesized derivatives, compound 24 showed the most potent antidepressant activity, and Compound 20 showed moderate antidepressant activity, which reduced the duration of immobility times to 35.42% and 31.97% at 100mg/kg dose level when compared to the control, respectively.

Conclusion: Compound 24 showed the highest MolDock score as well as found to be the most potent antidepressant agent.