Design, synthesis and evaluation of 1-(1,5-bis(4-substituted phenyl)-2-methyl-1-pyrrol-3-yl)--methylmethanamines as SERT inhibitors with potential antidepressant action.

BM212 is a potent anti-TB agent with pharmacophoric features similar to the antidepressant drug sertraline. The shape-based virtual screening of the DrugBank database on BM212 resulted in the identification of several CNS drugs with appreciable Tanimoto scores. The docking simulations also ascertained the selectivity of BM212 towards the serotonin reuptake transporter protein (SERT) with a docking score of -6.51 kcal mol. Based on the SAR data available for sertraline and other antidepressant drugs, we designed, synthesized and screened twelve 1-(1,5-bis(4-substituted phenyl)-2-methyl-1-pyrrol-3-yl)--methylmethanamines (SA-1 to SA-12) for SERT inhibition and antidepressant activity. The compounds were screened for 5HT reuptake inhibition using the platelet model. Among the screened compounds, (1-(1,5-bis(4-chlorophenyl)-2-methyl-1-pyrrol-3-yl)--methylmethanamine) showed the same serotonin uptake inhibition (absorbance 0.22) as that of the standard drug sertraline (absorbance 0.22). BM212 had an effect on 5-HT uptake, albeit a weaker one compared to the standard (absorbance 0.671). Further, SA-5 was screened for antidepressant activity using the unpredictable chronic mild stress (UCMS) protocol to induce depression in mice. The effect of BM212 and SA-5 on the behaviour of the animals was assessed and compared against the standard drug sertraline. SA-5 at 20 mg per kg body weight was found to have a statistically significant impact on the behaviour of depressed animals.