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. 2022 Oct 29;14(2):393–402. doi: 10.1039/d2md00243d

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

Anjani Uma Rani Wunnava a, Sony Priya Kurati a, Kilari Eswar Kumar b, Murali Krishna Kumar Muthyala a,✉
PMCID: PMC9945855  PMID: 36846366

Abstract

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−1. 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-1H-pyrrol-3-yl)-N-methylmethanamines (SA-1 to SA-12) for in vitro SERT inhibition and in vivo antidepressant activity. The compounds were screened for in vitro 5HT reuptake inhibition using the platelet model. Among the screened compounds, (1-(1,5-bis(4-chlorophenyl)-2-methyl-1H-pyrrol-3-yl)-N-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 in vivo 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.

Identification of SERT inhibition and antidepressant activity in diarylpyrrolemethylamines.graphic file with name d2md00243d-ga.jpg

1. Introduction

Depression is a psychological condition affecting about 5% of adults (approximately 280 million) around the world. It is a condition that significantly alters the behavioral interactions of the affected subjects, impacting their personal and emotional well-being.1 Certain classes of drugs, such as tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, glucocorticoids, neurokinin-1 antagonists, melanin-concentrating hormone antagonists, neurotrophins, 5-hydroxytryptamine receptor antagonists, phosphodiesterase inhibitors, and glutamatergic substances, have been explored as potential antidepressants. Duloxetine was the only drug to be approved for treating depression between 2000 and 2010. Brexanolone and esketamine were the only new anti-depressants to have been approved from 2010 to 2020.2

BM212 or 1-[1,5-bis(4-chlorophenyl)-2-methyl-1H-pyrrol-3-ylmethyl]-4-methylpiperazine (Fig. 1a) is a molecule that has been under investigation for over two decades as an inhibitor of the MmpL3 protein in Mycobacterium tuberculosis. This protein plays an essential role in the trans-membrane transport of precursors for the synthesis of the mycobacterial cell wall. The BM212 molecule was first investigated as an anti-tubercular moiety among compounds that had imidazole, pyrrole, toluidine and methanamine groups.3–5 Further structural optimization studies were carried out by replacing the methyl piperazine moiety with morpholine and thiomorpholine (Fig. 1b–e).6–8

Fig. 1. Structures of BM212 (1a), its analogues (1b–1e) and SA-5 (1f) employed in docking.

Fig. 1

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A pharmacophore model, which included a hydrophobic region with a pyrrole nucleus substituted with aryl or heteroaryl rings at the first and fifth positions, was established. The hydrogen bond forming quotient of a pharmacophore is determined by aliphatic secondary amines, such as N-methylpiperazine, morpholine or thiomorpholine.9

Drug repurposing has been one of the key research concepts explored in our laboratory.10–12 Anti-tubercular activity has been reported in drugs acting on the central nervous system, such as phenothiazines.13 A majority of commercially available selective serotonin reuptake inhibitors (SSRIs) have a common pharmacophore consisting of two aryl rings (hydrophobic region) separated by a short chain with a heteroatom (O or N) and a secondary or tertiary nitrogen atom.14,15 The similitude of the pharmacophoric features of BM212 to SSRIs prompted us to investigate its potential anti-depressant activity through serotonin reuptake inhibition using in silico, in vitro and in vivo screening techniques.

2. Results and discussion

2.1. Results of in silico screening

Shape-based virtual screening and ligand-based virtual screening were used as tools to assess the potential of the BM212 scaffold as a selective serotonin reuptake inhibitor. LiSiCA (Ligand Similarity using Clique Algorithm), an open-source shape-based virtual screening tool, was used to find structures that are complementary to BM212 in the Drug Bank database.16,17 The Tanimoto scores from the shape-based virtual screening were analysed, and it was found that more than 50% of the top-scoring hits were drugs acting on the central nervous system (antipsychotics and antidepressants).

The analogues of 1-[1,5-bis(4-chlorophenyl)-2-methyl-1H-pyrrol-3-ylmethyl]-4-methylpiperazine (BM212) with higher efficacy against Mycobacterium tuberculosis and a better pharmacokinetic profile have also been checked for their affinity against the target protein 6AWN. None of the other analogues (Fig. 1b–e) displayed greater binding affinity than BM212 towards the SERT protein.

A molecule was designed where the tertiary amine in BM212 was replaced with a methylamine group (1f); to mimic the methylamino group in fluoxetine and other SSRIs (Fig. 2).

Fig. 2. Rationale for the design of SA-5 from BM212.

Fig. 2

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The docking results of BM212 with selected receptors using AutoDock Vina show the greater affinity of the molecule towards the serotonin reuptake transporter (SERT) protein (Table 1). BM212 displayed a lower binding affinity (−5.31 kcal mol−1) to the dopamine (D2) receptor compared with the reference ligand haloperidol (−5.81 kcal mol−1). It displayed a larger binding affinity (−6.51 kcal mol−1, Fig. 3b) to SERT than paroxetine, the reference ligand (−6.30 kcal mol−1, Fig. 3a). When docked against the monoamine oxidase-B (MAO-B) receptor (3PO7), BM212 showed a binding energy of −5.26 kcal mol−1. With the histamine (H1) receptor, BM212 showed a lower binding affinity of −4.0 kcal mol−1 against the reference ligand, which showed a higher binding energy of −5.21 kcal mol−1. These results demonstrate the selectivity of BM212 towards the SERT protein.

Results of the docking analysis.

Target protein ID Binding energy of BM212 (kcal mol−1) Binding energy of the reference ligand (kcal mol−1) Hydrogen bonding interactions of BM212 Hydrogen bonding interactions of the reference ligand
6LUQ 18 (D2) −5.31 −5.81 Asp114, Tyr 437 Ser193
3PO7 (ref. 19) (MAO-B) −5.26 −3.11 Glu483 Glu34, Ala35, Arg36
6AWN 20 (SERT) −6.51 −6.30 Ala96, Asp98, Phe335 Asp98
3RZE 21 (H1) −4.08 −5.21 Asp107 Asp107
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Fig. 3. a: The binding pose of the co-crystallized ligand paroxetine with the serotonin reuptake transporter protein (6AWN). b: The binding pose of BM212 with the serotonin reuptake transporter protein (6AWN). c: The binding pose of analogue SA-5 with the serotonin reuptake transporter protein (6AWN).

Fig. 3

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1-(1,5-Bis(4-substituted phenyl)-2-methyl-1H-pyrrol-3-yl)-N-methylmethanamine, which has the tertiary amine in BM212 replaced by a secondary amine, showed a higher binding energy of −6.98 kcal mol−1 than the binding energy of −6.51 kcal mol−1 exhibited by BM212 (Fig. 3c).

2.2. Synthesis of BM212 and 1-(1,5-bis(4-substituted phenyl)-2-methyl-1H-pyrrol-3-yl)-N-methylmethanamines

BM212 was synthesized with a yield of 81% through a series of three steps (Scheme 1); step one involved the synthesis of arylpentane-1,4-diones by the Stetter reaction.22–25 The second step involved the formation of diarylpyrroles from arylpentan-1,4-diones via Paal Knorr synthesis.26 The third step involved the synthesis of the Mannich base by the Mannich reaction.27

Scheme 1. Scheme of the synthesis of BM212 and diarylpyrrolemethylamines.22–30.

Scheme 1

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The 1-(1,5-bis(4-substituted phenyl)-2-methyl-1H-pyrrol-3-yl)-N-methylmethanamines (Table 2) were synthesized by a series of four steps (Scheme 1). The first step involved the Stetter reaction, and the second step involved Paal Knorr synthesis. The diarylpyrroles obtained were converted to diarylpyrrole carboxaldehydes by Vilsmeier Haack formylation.28,29 These aldehydes were subjected to reductive amination to obtain diarylpyrrole methylamines with yields above 75%.30

List of the diarylpyrrole methylamines synthesized.

graphic file with name d2md00243d-u1.jpg
Compound code R1 R2 R3
SA-1 Cl Cl H
SA-2 Cl Cl Cl
SA-3 Cl Cl CH3
SA-4 H Cl H
SA-5 H Cl Cl
SA-6 H Cl CH3
SA-7 Cl H H
SA-8 Cl H Cl
SA-9 Cl H CH3
SA-10 F H H
SA-11 F H Cl
SA-12 F H CH3
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The detailed experimental procedures of the syntheses have been provided in section 1 of ESI.† The progress of the reactions was monitored by TLC. The compounds were characterized by ESI-MS, 1H NMR, 13C NMR and elemental analysis.

2.3. Results of the in vitro effect of the target compounds on 5-HT reuptake in platelets

Almost ninety percent of the serotonin in the body is present in the cardiovascular system. There are two distinct pools of serotonin in the body: one in the central nervous system and the other in the blood. It regulates platelet function and vascular tone. Platelets are the carriers and storage sites of serotonin in the periphery. They express 5-HT2A receptors and the serotonin reuptake transporter (SERT) protein. The SERT protein is involved in the transport of serotonin across membranes.31,32 Research by Lesch et al. indicates that the SERT proteins in the brain and platelets are identical.33

Platelets have served as an uncomplicated and replicable model for studying the effects of antidepressants on serotonin reuptake. Platelets are more easily accessible than other cells that need to be cultured using laborious and expensive equipment and protocols.34–38

Platelets were used as the model to study the effect of the target compounds on serotonin reuptake by the enzyme-linked immunoassay (ELISA) method.39 The standard curve constructed using serotonin standard solutions from 25 ng mL−1 to 400 ng mL−1 showed an r value of 0.97 and an r2 value of 0.94. The details of the procedure used in this study are discussed in ESI.†

Platelet-rich plasma (of about 10 mL volume) was used in the experiments. The basal value of serotonin in 200 μL of platelet-rich plasma (negative control) was determined. The absorbance of the blank sample consisting only of the reagents used was also measured. The platelets were incubated with increasing concentrations of serotonin (50 ng mL−1 and 200 ng mL−1) to estimate uptake by the platelets.

After ascertaining the uptake of serotonin in the lab based on absorbance values, the effect of the standard drug sertraline on serotonin uptake was studied. Platelets were incubated with sertraline (100 ng mL−1) or a selective serotonin reuptake inhibitor (SA1–SA12 and BM212 at 100 ng mL−1) followed by serotonin (200 ng mL−1) to identify the level of 5-HT uptake inhibition. Inhibition of serotonin uptake was observed in platelets incubated with sertraline (absorbance = 0.22) compared with those incubated only with serotonin (absorbance = 1.254).

The protocol was successful in identifying the uptake of 5-HT (serotonin) by platelets at the tested concentration. An increase in the intracellular concentration of serotonin was observed with an increase in extracellular concentration from 50 ng mL−1 (absorbance = 0.573) to 200 ng mL−1 (absorbance = 1.254). The 1-(1,5-bis(4-substituted phenyl)-2-methyl-1H-pyrrol-3-yl)-N-methylmethanamines tested for their serotonin reuptake inhibitory potential showed some degree of reuptake inhibition (Fig. 4 and Table 3). The compound SA-5 with a chlorine atom each at R2 and R3 manifested the most substantial 5-HT reuptake inhibition (absorbance = 0.22) among the compounds tested. This value is commensurate with the 5-HT reuptake inhibition effect exhibited by the standard drug sertraline (absorbance = 0.220). BM212 showed a lower degree of 5-HT reuptake inhibition (absorbance = 0.672) than sertraline (absorbance = 0.220).

Fig. 4. A plot of the absorbance values of the different compounds tested.

Fig. 4

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Absorbance values from the ELISA test.

Sample Absorbance 1 Absorbance 2
Blank 0.010 0.011
Negative control 0.219 0.221
5-HT (200 ng mL−1) and platelets 1.240 1.268
5-HT (50 ng mL−1) and platelets 0.584 0.562
Positive control 0.221 0.219
SA-1 0.243 0.238
SA-2 0.237 0.228
SA-3 0.255 0.246
SA-4 0.252 0.248
SA-5 0.222 0.224
SA-6 0.264 0.254
SA-7 0.277 0.277
SA-8 0.257 0.268
SA-9 0.284 0.28
SA-10 0.314 0.321
SA-11 0.278 0.291
SA-12 0.316 0.322
BM212 0.681 0.662
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2.4. In vivo studies

Unpredictable chronic mild stress adapted from Burstein et al. was used for assessing the anti-depressant potential of the target compounds (BM212 and SA-5).40,41

Nest building test (NBT),42–44 tail suspension test (TST),45–47 forced swim test (FST)48–50 and the elevated plus maze (EPM)51,52 were used to evaluate the effect of the test compounds on the different groups. Animals treated with the standard drug sertraline built nests enveloping the animal, whereas animals from the vehicle group did not engage in nest-building activity or built flat nests. All animals administered with the test compounds engaged in the nest-building activity (Fig. 5a).

Fig. 5. a: Scores from NBT. b: Scores from TST. c: Scores from FST. d: Ratios of the number of open-arm entries to closed-arm entries. e: Ratios of time spent in open arms to time spent in closed arms. Results from the in vivo studies. BM212 (L.D): BM212 low dose, BM212 (H.D): BM212 high dose, SA-5 (L.D): SA-5 low dose, SA-5 (H.D): SA-5 high dose.

Fig. 5

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The animals from groups 3 (BM212 low dose), 4 (BM212 high dose), 5 (SA-5 low dose) and 6 (SA-5 high dose) showed mean immobility times of 177.80, 95.383, 96.80 and 33.1667 seconds, respectively. The vehicle group (group 2) exhibited a mean immobility time of 236.80 seconds. The groups treated with the test compounds demonstrated a significantly greater engagement in escape efforts than the control group. This is supported by results from the statistical analysis (Welch's ANOVA): W = 40.31 (DFn = 5.000, DFd = 13.74, P < 0.05) (Fig. 5b).

In the forced swim test, the mean immobility time of group 2 was 18.5 seconds against 137.6 seconds of the control group (treated with the vehicle). The animals from groups 3, 4, 5 and 6 showed mean immobility times of 95.2, 60.8, 70.3 and 10.7 seconds, respectively. These results along with the results from the statistical analysis [W = 194.4 (DFn = 5.000, DFd = 13.83), P < 0.05] evidence that the test compounds had an elevating influence on the desire of the treated animals to escape stress (Fig. 5c).

The scores from the elevated plus maze test concurred with the behavior exhibited in the other behavioral analyses. The control group had the least ratio of open-arm entries to closed-arm entries, signifying the unwillingness of the animals to explore the open arm (Fig. 5d). The group treated with the standard drug had a higher mean ratio of 0.8692, indicating the standard group had more open-arm entries than the control group. The mice in the treatment groups were less anxious in venturing out onto the open arms [W = 4.833 (DFn = 5.000, DFd = 13.77), P < 0.05]. Moreover, the control group had the lowest mean ratio of time spent in the open arm to time spent in the closed arm compared with that of the standard group (Fig. 5e). The animals from group 6 spent a longer time exploring the open arms compared with the control group. There was a significant change in the anxiety of mice in the treatment groups in terms of the number of open-arm entries and the time spent in the open arms.

3. Conclusions

The findings from the in vivo studies of the test compounds match well with the in silico and in vitro assay results. SA-5 shows a statistically significant [P < 0.05] impact on the behaviour of animals subjected to unpredictable chronic mild stress, similar to the shift in behavior observed upon treatment with the standard drug sertraline.

These results indicate that the ADME profile of SA-5 should be assessed for further optimization of the molecule. Oxidative stress is one of the biomarkers of depression, and psychotropic drugs, such as fluoxetine, have been found to have a mitigating effect on oxidative stress in animal models. The antioxidant effect of the 1-(1,5-bis(4-substituted phenyl)-2-methyl-1H-pyrrol-3-yl)-N-methylmethanamines needs to be explored.53

4. Experimental section

4.1. Docking protocol

The structures of the target proteins dopamine D2 (6LUQ),18 monoamine oxidase inhibitor (3PO7),19 serotonin reuptake transporter protein (6AWN)20 and histamine H1 (3RZE)21 were accessed from the protein databank and validated using the Molprobity server.54

The docking protocol was implemented for the selected ligands (Fig. 1) using AutoDock Vina.55 The binding energies of BM212 and its analogues were compared against the docking score of the co-crystallized ligand.

Protein and ligand preparation was done by following protocols from the literature, as cited in the Results and discussion section.56 The results were analysed using Pymol.57 The grid dimensions generated using the docking protocol are presented in Table 4. Validation of the docking protocol was done by correlating the RMSD (root mean square deviation) values from the best binding pose of the ligand and the docked pose of the co-crystallised ligand. The interactions of the docked ligands with the target proteins were visualised using Pymol viewer 2.4.1.

Grid dimensions of the proteins selected for the in silico screening experiment.

Target protein Center Size
X Y Z X Y Z
6LUQ 5.731 5.805 −7.695 40 40 40
3PO7 51.113 150.634 31.061 40 40 40
6AWN 32.783 181.142 145.705 40 40 40
3RZE 14.806 35.041 19.011 40 40 40
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The NMR spectra of the synthesized compounds are included as ESI.†

4.2. Physical constants and characterization of BM212

1-[1,5-Bis(4-chlorophenyl)-2-methyl-1H-pyrrol-3-ylmethyl]-4-methylpiperazine

Yield 81%; M.pt. 180.2–182.4 °C; IR (KBr) νmax cm−1 (C–Cl str) 832.20, (Pyr C–N str) 1093.06, (Ar C Created by potrace 1.16, written by Peter Selinger 2001-2019 C str) 1588.59, (Al C–H str) 2938.68, (Ar C–H str) 3379.79; 1H NMR (400 MHz, CDCl3) δ 2.112 (s, 3H), 2.311 (s, 3H), 2.52 (bs, 8H), 3.505 (s, 2H), 6.332 (s, 1H), 7.058 (m, 4H), 7.083 (m, 1H), 7.266 (s, 1H), 7.317 (d, 1H, J = 2 Hz); 13C NMR (100 MHz, CDCl3) δ 11.18, 46.05, 52.78, 55.18, 55.44, 111.69, 117.00, 127.86, 128.28, 128.76, 128.97, 129.33, 129.72, 131.58, 131.83, 133.39, 137.79; ESIMS (M + H) m/z 414.2.

4.3. Physical constants and characterization of diarylpyrrole methylamines

[5-(2,4-Dichlorophenyl)-2-methyl-1-phenyl-1H-pyrrol-3ylmethyl]methylamine (SA1)

Yield 90%; gummy solid; IR (KBr) νmax cm−1 (C–Cl str) 832.14, (Pyr C–N str) 1051.88, (Ar C Created by potrace 1.16, written by Peter Selinger 2001-2019 C str) 1584.10, (Ar C–H str) 3330.26, (N–H str) 3364.42; 1H NMR (400 MHz, CDCl3) δ 2.131 (s, 3H), 2.581 (s, 3H), 3.926 (s, 2H), 6.422 (s, 1H), 7.009 (d, 4H, J = 8.4 Hz), 7.069 (m, 1H), 7.311 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 10.93, 32.06, 44.67, 112.31, 112.67, 126.65, 129.11, 129.29, 129.48, 130.20, 130.49, 133.33, 133.60, 134.01, 134.98, 136.61, 177.63; ESIMS (M + H) m/z 344.1.

[1-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-2-methyl-1H-pyrrol-3ylmethyl]methylamine (SA2)

Yield 89%; gummy solid; IR (KBr) νmax cm−1 (C–Cl str) 816.35, (Pyr C–N str) 1094.72, (Ar C Created by potrace 1.16, written by Peter Selinger 2001-2019 C str) 1580.17, (Ar C–H str) 3374.46, (N–H str) 3406.90; 1H NMR (400 MHz, CDCl3) δ 2.137 (s, 3H), 2.317 (s, 3H), 3.739 (s, 2H), 6.356 (s, 1H), 7.079 (m, 7H); 13C NMR (100 MHz, CDCl3) 11.03, 35.48, 47.43, 111.16, 112.76, 117.46, 125.92, 127.93, 128.10, 128.14, 129.18, 129.41, 129.62, 132.80, 132.24, 136.11, 136.85; ESIMS (M + H) m/z 378.0.

[5-(2,4-Dichlorophenyl)-2-methyl-1-p-tolyl-1H-pyrrol-3ylmethyl]methylamine (SA3)

Yield 84%; gummy solid; IR (KBr) νmax cm−1 (C–Cl str) 838.65, (Pyr C–N str) 1095.19, (Ar C Created by potrace 1.16, written by Peter Selinger 2001-2019 C str) 1579.24, (Ar C–H str) 3374.94, (N–H str) 3416.62; 1H NMR (400 MHz, CDCl3) δ 2.118 (s, 3H), 2.335 (s, 3H), 2.574 (s, 3H), 3.916 (s, 2H), 6.414 (s, 1H), 6.957 (m, 2H), 7.014 (m, 2H), 7.098 (d, 2H, J = 8.4 Hz), 7.300 (d, 1H, J = 2 Hz); 13C NMR (100 MHz, CDCl3) δ 10.93, 21.08, 32.28, 44.94, 111.96, 112.62, 127.82, 129.31, 129.45, 130.21, 130.95, 133.34, 134.93, 135.51, 137.48; ESIMS (M + H) m/z 358.1.

[5-(4-Chlorophenyl)-2-methyl-1-phenyl-1H-pyrrol-3ylmethyl]methylamine (SA4)

Yield 90%; gummy solid; IR (KBr) νmax cm−1 (C–Cl str) 814.37, (Pyr C–N str) 1050.43, (Ar C Created by potrace 1.16, written by Peter Selinger 2001-2019 C str) 1588.90, (Ar C–H str) 3390.40, (N–H str) 3423.4; 1H NMR (400 MHz, CDCl3) δ 2.136 (s, 3H), 2.638 (s, 3H), 4.027 (s, 2H), 6.486 (s, 1H), 6.955 (m, 2H), 7.015 (td, 1H, J = 1.6 Hz, 7.6 Hz), 7.166 (m, 3H), 7.336 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 10.93, 31.22, 44.25, 111.97, 115.41, 115.64, 123.56, 123.59, 127.62, 127.71, 128.06, 128.62, 128.70, 128.863, 131.31, 131.41, 131.44; ESIMS (M + H) m/z 310.1.

[1,5-Bis-(4-chlorophenyl)-2-methyl-1H-pyrrol-3ylmethyl]methylamine (SA5)

Yield 79%; M.pt. 121.3–124.7 °C; IR (KBr) νmax cm−1 (C–Cl str) 823.16, (Pyr C–N str) 1057.41, (Ar C Created by potrace 1.16, written by Peter Selinger 2001-2019 C str) 1587.82, (Ar C–H str) 3391.86, (N–H str) 3420.1; 1H NMR (400 MHz, CDCl3) δ 2.102 (s, 3H), 2.548 (s, 3H), 3.736 (s, 2H), 6.426 (s, 1H), 6.963 (d, 2H, J = 8.4 Hz), 7.100 (d, 2H, J = 8.4 Hz), 7.144 (m, 2H), 7.372 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 10.95, 35.12, 46.97, 110.06, 117.55, 127.71, 128.15, 128.49, 128.55, 128.75, 129.15, 129.82, 131.49, 131.64, 132.26, 139.05; ESIMS (M + H) m/z 344.0.

[5-(4-Chlorophenyl)-2-methyl-1-p-tolyl-1H-pyrrol-3ylmethyl]methylamine (SA6)

Yield 90%; gummy solid; IR (KBr) νmax cm−1 (C–Cl str) 816.35, (Pyr C–N str) 1058.41, (Ar C Created by potrace 1.16, written by Peter Selinger 2001-2019 C str) 1586.71, (Ar C–H str) 3389.72, (N–H str) 3417.23; 1H NMR (400 MHz, CDCl3) δ 2.098 (s, 3H), 2.527 (s, 3H), 3.087 (s, 3H), 3.695 (s, 2H), 6.396 (s, 1H), 6.955 (d, 2H, J = 8 Hz), 7.090 (dd, 4H, J = 8 Hz, 16 Hz), 7.364 (d, 2H, J = 8 Hz); 13C NMR (100 MHz, CDCl3) δ 10.94, 13.09, 35.35, 47.05, 110.39, 118.33, 128.32, 128.85, 129.13, 129.39, 129.55, 129.68, 131.32, 131.36, 131.77, 132.27, 133.53, 137.61; ESIMS (M + H) m/z 324.1.

[5-(2-Chlorophenyl)-2-methyl-1-phenyl-1H-pyrrol-3ylmethyl]methylamine (SA7)

Yield 90%; gummy solid; IR (KBr) νmax cm−1 (C–Cl str) 827.48, (Pyr C–N str) 1089.21, (Ar C Created by potrace 1.16, written by Peter Selinger 2001-2019 C str) 1594.43, (Ar C–H str) 3379.03, (N–H str) 3421.91; 1H NMR (400 MHz, CDCl3) δ 2.110 (s, 3H), 2.549 (s, 3H), 3.711 (s, 2H), 6.416 (s, 1H), 6.973 (d, 2H, J = 8.4 Hz), 7.108 (m, 2H), 7.138 (dd, 2H, J = 1.6 Hz, 6.4 Hz), 7.397 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 8.40, 33.09, 44.78, 107.47, 115.88, 125.12, 125.61, 125.87, 125.97, 126.20, 126.32, 126.59, 127.01, 128.75, 128.89, 129.18, 129.62, 136.59; ESIMS (M + H) m/z 310.1.

[1-(4-Chlorophenyl)-5-(2-chlorophenyl)-2-methyl-1H-pyrrol-3ylmethyl]methylamine (SA8)

Yield 90%; M.pt. 132.6–134.1 °C; IR (KBr) νmax cm−1 (C–Cl str) 836.44, (Pyr C–N str) 1091.76, (Ar C Created by potrace 1.16, written by Peter Selinger 2001-2019 C str) 1537.79, (Ar C–H str) 3300.85, (N–H str) 3432.65; 1H NMR (400 MHz, CDCl3) δ 2.20 (s, 3H), 2.658 (s, 3H), 4.067 (s, 2H), 6.516 (s, 1H), 7.031 (d, 2H, J = 8.4 Hz), 7.101 (m, 2H), 7.184 (m, 1H), 7.275 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 11.21, 36.11, 44.54, 107.10, 112.07, 124.77, 126.26, 128.95, 129.07, 129.36, 131.65, 132.83, 133.08, 142.75, 163.72; ESIMS (M + H) m/z 344.0.

[5-(2-Chlorophenyl)-2-methyl-1-p-tolyll-1H-pyrrol-3ylmethyl]methylamine (SA9)

Yield 78%; gummy solid; IR (KBr) νmax cm−1 (C–Cl str) 831.40, (Pyr C–N str) 1051.07, (Ar C Created by potrace 1.16, written by Peter Selinger 2001-2019 C str) 1591.07, (Ar C–H str) 3333.91, (N–H str) 3418.33; 1H NMR (400 MHz, CDCl3) δ 2.140 (s, 3H), 2.321 (s, 3H), 2.615 (s, 3H), 4.033 (s, 2H), 6.410 (s, 1H), 6.966 (d, 3H, J = 8 Hz), 7.099 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 10.95, 21.07, 31.52, 44.52, 111.10, 111.53, 126.00, 127.87, 128.54, 129.29, 129.42, 130.17, 130.47, 132.25, 132.83, 134.36, 135.62, 137.31; ESIMS (M + H) m/z 324.1.

[5-(2-Fluorophenyl)-2-methyl-1-phenyl-1H-pyrrol-3ylmethyl]methylamine (SA10)

Yield 90%; gummy solid; IR (KBr) νmax cm−1 (Pyr C–N str) 1108.37, (Ar C Created by potrace 1.16, written by Peter Selinger 2001-2019 C str) 1590.51, (Al C–H str) 2935.18, (Ar C–H str) 3334.62, (N–H str) 3419.32; 1H NMR (400 MHz, CDCl3) δ 2.157 (s, 3H), 2.600 (s, 3H), 3.957 (s, 2H), 6.426 (s, 1H), 7.119 (m, 6H), 7.302 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 10.97, 23.47, 31.87, 111.71, 126.00, 127.44, 128.16, 128.57, 128.64, 129.44, 129.89, 132.19, 132.80, 134.34, 138.80; ESIMS (M + H) m/z 294.1.

[1-(4-Chlorophenyl)-5-(2-fluorophenyl)-2-methyl-1H-pyrrol-3ylmethyl]methylamine (SA11)

Yield 89%; gummy solid; IR (KBr) νmax cm−1 (Pyr C–N str) 1098.32, (Ar C Created by potrace 1.16, written by Peter Selinger 2001-2019 C str) 1593.51, (Al C–H str) 2937.18, (Ar C–H str) 3324.42, (N–H str) 3415.45; 1H NMR (400 MHz, CDCl3) δ 2.072 (s, 3H), 2.405 (s, 3H), 3.670 (s, 2H), 6.378 (s, 1H), 7.104 (m, 3H), 7.158 (d, 2H, J = 8.8 Hz), 7.242 (m, 1H), 7.458 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 11.09, 29.71, 38.16, 112.07, 115.73, 119.66, 120.71, 123.77, 126.49, 127.44, 129.0, 129.26, 131.47, 133.57, 134.40, 137.23, 143.07 ESIMS (M + H) m/z 328.1.

1-[5-(2-Fluorophenyl)-2-methyl-1-p-tolyl-1H-pyrrol-3-ylmethyl]methylamine (SA12)

Yield 85%; gummy solid; IR (KBr) νmax cm−1 (Pyr C–N str) 1087.22, (Ar C Created by potrace 1.16, written by Peter Selinger 2001-2019 C str) 1589.51, (Al C–H str) 2945.18, (Ar C–H str) 3336.62, (N–H str) 3418.33; 1H NMR (400 MHz, CDCl3) δ 2.063 (s, 3H), 2.3030 (s, 3H), 2.487 (s, 3H), 3.837 (s, 2H), 6.411 (s, 1H), 7.005 (d, 2H, J = 8.4 Hz), 7.081 (m, 3H), 7.189 (d, 3H, J = 8.8 Hz); 13C NMR (100 MHz, CDCl3) δ 15.94, 19.31, 39.56, 51.14, 117.29, 120.71, 120.94, 122.08, 125.83, 129.44, 131.08, 134.19, 134.36, 134.78, 136.46, 134.78, 137.18, 142.52; ESIMS (M + H) m/z 308.1.

4.4. In vitro assay

Sertraline HCl was obtained as a gift from Harika Drugs Private Limited, Hyderabad, India. The human serotonin ELISA kit was obtained from MyBioSource (MBS160020). The Alere AM1200 microplate reader was used for reading the results. The detailed procedure of the in vitro assay is included as ESI† (section 3).

4.5. In vivo assay

Acute toxicity tests were conducted by following OECD guideline 423. Male Swiss Albino mice were used for ascertaining the potential anti-depressant activity of the target compounds. The unpredictable chronic mild stress protocol described by Burstein et al. was used to induce depression in three-week-old mice weighing around 10–12 g.40,41 The animals were subjected to an induction period of 28 days followed by a treatment period of 21 days. The animals were continuously monitored during this period.

All animal procedures were performed in accordance with the Guidelines for Care and Use of Laboratory Animals of Andhra University and approved by the Institutional Animal Ethics Committee of Andhra University College of Pharmaceutical Sciences.

Dosage

Group 1: treated with sertraline 10 mg kg−1 b.w (standard drug, b.w – body weight) in 1% w/v methylcellulose in water.

Control/group 2: treated with ≤0.2 mL per day per animal of 1% w/v methylcellulose in water.

Group 3: treated with BM212, 10 mg kg−1 b.w in 1% w/v methylcellulose in water.

Group 4: treated with BM212, 20 mg kg−1 b.w in 1% w/v methylcellulose in water.

Group 5: treated with SA-5, 10 mg kg−1 b.w in 1% w/v methylcellulose in water.

Group 6: treated with SA-5, 20 mg kg−1 b.w in 1% w/v methylcellulose in water.

Nest building test (NBT),42–44 tail suspension test (TST),45–47 forced swim test (FST)48–50 and elevated plus maze (EPM)51,52 were employed to test the effectiveness of treatment across groups. The detailed procedures of induction and testing are included in the ESI† (section 4). The results from the experiments have been represented as graphs using the software Graph Pad Prism (version 9.0).

Author contributions

Anjani Uma Rani Wunnava designed and executed the study, collected the data and analysed it and authored the article. Sony Priya Kurati helped in data collection. Eswar Kumar Kilari was instrumental in designing the in vivo and in vitro study. Murali Krishna Kumar Muthyala was involved in designing the study, analysing the data and correction of the manuscript.

Conflicts of interest

There are no conflicts to declare.

Supplementary Material

MD-014-D2MD00243D-s001

Acknowledgments

The authors acknowledge the funding from Department of Science and Technology, India without which this work would not have been possible.

†

Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d2md00243d

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