Description

Our present study focuses on synthesis, characterisation and antipsychotic evaluation of 6-fluoro-3-(piperidin-4-yl) benzo d]isoxazole derivatives. A new series of benzisoxazole derivatives were synthesized, which are close structural analogs of risperidone, a known second generation antipsychotic drug. The structures of the newly synthesized molecules were confirmed by 1) NMR, LC MS, FTIR and elemental analysis. In silico analysis of the parameters of lipinski's rule of five, along with polar surface area (PSA), absorption%(%ABS), drug likeness indicated that all the synthesized compounds may have prospective role as antipsychotic molecules. In silico structure-toxicity predictions and bioactive scores of synthesized molecules showed identical properties as that of known antipsychotic drugs haloperidol and risperidone. The antipsychotic behavioural studies also indicate the antagonistic property of synthesized molecules (S1-S4) to dopamine D2 and serotonin receptors and also lower propensity to caused extrapyramidal symptoms (EPS). The possibility and efficiency of these synthesized molecules to penetrate through the Blood Brain Barrier is of utmost importance to determine its treatment efficacy. In this line of investigation, in the present study, in silico and in vitro methods are employed to evaluate the permeability in comparison with that of standard antipsychotic drugs, risperidone and haloperidol. In vitro analysis was done by parallel artificial membrane permeability assay (PAMPA) in PBS, where in permeability of S2(8.3x10-6) and S3(6.6x10-6) molecules showed higher permeability than known standards warfarin(1x10-6), risperidone(2.3x10-6) and haloperidol(3.5x10-6), and the molecules exhibited recovery above 50% and in silico studies also showed high permeability rate