Barium silicate nanoparticles, an efficient catalyst for one-pot green synthesis of α-benzyl amino coumarin derivatives as potential chemotherapeutic agents

Abstract

A new, simple, and efficient method for synthesis of α-benzyl amino coumarin and its derivatives (1–24) is described via a one-pot, three-component condensation of aromatic aldehydes, amine, and 4-hydroxycoumarin under green chemistry conditions: water as a solvent and BaSiO₃ nanoparticles as catalyst. BaSiO₃ nanoparticles and all synthesized derivatives were characterized by multiple methods including; XRD, NMR, and FE-SEM. This method which gives higher yields, is also less expensive, and more environmentally friendly compared with other methods in the literature. In silico physicochemical and pharmacokinetics analyses were done on all synthesized compounds and indicated that these α-benzyl amino coumarins would be effective scaffolds for the future development of chemotherapeutic agents.

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1. Introduction

Recently, 4-hydroxycoumarin and its derivatives have been of great interest due to their special role in natural and synthetic organic chemistry.¹ Furthermore, coumarin is a suitable scaffold for chemical reactions in several studies, due to its hydroxyl and carbonyl groups adjacent to the α-position. Consequently, the 4-hydroxycoumarin and its derivatives have broad spectrum pharmacological properties including: antioxidant,² antimicrobial,³ HIV protease inhibitors,⁴ antibacterial,⁵ antifungal,⁶ antitumor,⁷ and anticoagulant⁸ activities. Thus, the development of coumarin-containing compounds for drug discovery has recently drawn much attention. α-Benzyl amino coumarins are one of the most useful products resulting from 4-hydroxycoumarin's reactions. These compounds have been developed with various methods such as using: non-ionic surfactant in aqueous media,⁹ catalyst-free conditions in dichloromethane,¹⁰ InCl₃ in toluene,^11,12 chlorosulfonic acid,¹³ TiO₂ nanocatalyst,¹⁴ catalyst-free in ethanol solvent,¹⁵ {[1,4-DHPyrazine][C(CN)₃]₂} as a new nanostructured molten salt (NMS) catalyst,¹⁶ catalyst-free in CH₂Cl₂ (ref. 17), [Et₃NH][HSO₄] ionic liquid,¹⁸ Fe₃O₄@ZrO₂/SO₄⁻² heterogeneous nanocatalyst in CH₃CN,¹⁹ β-cyclodextrin based nanosponge in ethanol,²⁰ free-catalyst in CH₃CN,²¹ nano crystalline ZnO,²² NaOH.²³ However, most of these methods rely on multistep reactions and complex synthetic pathways with prolonged reaction times, low yields, expensive and harsh reaction conditions, as well as toxic catalysts. Thus, the development of new methods without such limitations is of great importance to prepare such heterocycles, found in natural products. Furthermore, multicomponent reactions (MCRs) are generating considerable interest in pharmaceutical chemistry to synthesize diverse structures of bioactive heterocycles, involving three or more reactants in one-pot reactions.²⁴ Due to non-toxic and unique nature of water, there has been a rapid rise in the use of aqueous environment instead of conventional organic solvents in organic synthesis, especially in the MCRs.

In the present study, due to the importance of α-benzyl amino coumarin scaffolds as a significant class of heterocycles in medicinal chemistry, a new, highly efficient, mild, and eco-friendly synthesis protocol is reported. Condensation between 4-hydroxycoumarin, an aliphatic amine, and a vast range of aromatic aldehydes using barium silicate nanoparticles as a heterogeneous, effective catalyst, is applied to obtain α-benzyl amino coumarin compounds (Scheme 1).

Scheme 1 Synthesis of α-benzyl amino coumarin derivatives.

Furthermore, regarding the significant biological profiles of the coumarin-bearing structures, the physicochemical and pharmacokinetic properties of these α-benzyl amino coumarins were examined through in silico analysis, to identify them as suitable biological candidates for future evaluations.

2. Result and discussion

2.1. Chemistry

In order to determine the crystalline structure and phase composition of the BaSiO₃ nanopowder, X-ray diffraction (XRD) analysis using Cu-Kα radiation (Fig. 1). The average size was measured by the Sherer equation by measuring the highest peak (peak appearing at 22.0° (2° theta)); the XRD spectrum was 30 nm.

Fig. 1 XRD pattern of BaSiO₃ Nanoparticles.

A particle size distribution diagram was plotted through the data obtained from dynamic light scattering (DLS) analysis and showed the particles were dispersed in the range of 45–140 nm. According to the diagram, the average particle size was 74 nm (Fig. 2). The energy-dispersive X-ray spectroscopy analysis (EDAX) demonstrated the elements in the composition and the weight percentage of each (17.16% Si, 57.35% Ba, and 26.49% O), which confirmed the proposed structure of the composition as BaSiO₃. The TEM Photograph displayed unregular and chaotic particles with nanometer size (Fig. 2).

Fig. 2 DLS, EDS analyses, and TEM photographs of BaSiO₃ nanoparticles.

Fig. 3, represented the FT-IR spectra of fresh and recovered BaSiO₃ which was used for the evaluation of functional groups presented in the structure of the catalyst. The samples contained metal–oxygen bonds which showed stretching and bending vibrations. The broad adsorption peak which appeared in the 3200–3700 cm⁻¹ was corresponded to stretching vibrations of Si–OH and –OH groups presented in BaSiO₃ and adsorbed water. The adsorption peaks at 1637, 1448, and 1083 cm⁻¹ could be assigned to the presence of Si–O (stretching vibration), and Si–O–Si (asymmetric stretching vibration) bonds. The peaks entered at 798 and 477 cm⁻¹ were assigned to be related to Si–O–Ba stretching vibration and Ba–O bonds (Fig. 3).

Fig. 3 FT-IR analysis of BaSiO₃ nanoparticles.

To find the optimal conditions for the synthesis of α-benzyl amino coumarins, the synthesis of 4-hydroxy-3-(phenyl(piperidine-1-yl)methyl)-2H-chromen-2-one (compound A₁), by the reaction of benzaldehyde (1.2 mmol), pyridine (1.2 mmol) and 4-hydroxy-coumarin (1 mmol), was selected as a model reaction.

This reaction was performed in water as a green solvent, as well as in the presence of various organic solvents, using 0.56 mg of barium silicate nanoparticle (1–8) (Table 1).

Table 1 Optimization of the reaction conditions in the synthesis of 4-hydroxy-3-(phenyl(piperidine-1-yl)methyl)-2H-chromium-2-one^a

Entry	Catalyst (mmol)	T (°C)	Solvent (5 ml)	Yield^b (%)
a Time for reaction: 2 hours.b Isolated yield.
1	0.56	r.t.	—	10
2	0.56	r.t.	n-Hexane	—
3	0.56	r.t.	CH2Cl2	—
4	0.56	r.t.	Et2O	—
5	0.56	r.t.	EtOAc	—
6	0.56	r.t.	EtOH	10
7	0.56	r.t.	MeOH	40
8	0.56	r.t.	H2O	79
9	0.14	r.t.	H2O	51
10	0.28	r.t.	H2O	85
11	1	r.t.	H2O	85

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As seen from the results represented in Table 1, when the model reaction was carried out in the presence of organic solvents, it did not lead to the production of A₁ products but rather led to the formation of 3,3′-(phenyl methylene) bis(4-hydroxy-2H-chromen-2-one) (B₁) as a final product. This finding showed that A products were only obtained in highly aqueous media. (Scheme 2). The different amounts of barium silicate nanoparticle in the model reaction were also investigated (8–11), which indicated that using 0.28 mg of this catalyst increased the yield of the reaction properly.

Scheme 2 Multi-component reaction of benzaldehyde, piperidine, and 4-hydroxycomarin in water and organic solvents.

Overall, the use of 0.28 mg of designed catalysts in aqueous media was selected as an optimal condition for the model reaction to synthesize various derivatives of α-benzyl amino coumarin compounds using cycloaliphatic amines, different aromatic and aliphatic aldehydes, A₁–A₃₀ (Table 2). As shown in Table 2, unfortunately, the aliphatic aldehydes were unreactive and could not be matched for the given reaction to form targeted molecules. Only aromatic aldehydes generated the desired compounds, A₁–A₂₄ (Table 2).

Table 2 Synthesis of α-benzyl amino coumarin derivatives using barium silicate nanoparticles

Entry	Aldehyde	Amine	Product	Time (min)	Yield^a (%)
a Isolated yield.
1	Benzaldehyde	Piperidine	A1	30	85
2	2-Chlorobenzaldehyde	Piperidine	A2	60	87
3	4-Chlorobenzaldehyde	Piperidine	A3	40	70
4	2-Methylbenzaldehyde	Piperidine	A4	70	84
5	4-Methylbenzaldehyde	Piperidine	A5	60	81
6	4-Methoxybenzaldehyde	Piperidine	A6	70	70
7	4-tert-Butylbenzaldehyde	Piperidine	A7	40	89
8	3-Nitrobenzaldehyde	Piperidine	A8	25	90
9	2,4-Dichlorobenzaldehyde	Piperidine	A9	75	61
10	4-Bromobenzaldehyde	Piperidine	A10	40	90
11	Benzaldehyde	Pyrrolidine	A11	45	82
12	4-Bromobenzaldehyde	Pyrrolidine	A12	30	90
13	4-Chlorobenzaldehyde	Pyrrolidine	A13	30	93
14	4-Nitrobenzaldehyde	Pyrrolidine	A14	25	88
15	4-Methylbenzaldehyde	Pyrrolidine	A15	65	89
16	4-Methoxybenzaldehyde	Pyrrolidine	A16	80	95
17	3-Nitrobenzaldehyde	Pyrrolidine	A17	30	92
18	Benzaldehyde	Morpholine	A18	45	93
19	4-Bromobenzaldehyde	Morpholine	A19	40	90
20	4-Chlorobenzaldehyde	Morpholine	A20	35	98
21	4-Nitrobenzaldehyde	Morpholine	A21	30	78
22	4-Methylbenzaldehyde	Morpholine	A22	55	90
23	2,4-Dichlorobenzaldehyde	Morpholine	A23	45	92
24	3,5-Dchlorobenzaldehyde	Morpholine	A24	30	89
25	Butyraldehyde	Piperidine	A25	120	—
26	Butyraldehyde	Pyrrolidine	A26	120	—
27	Butyraldehyde	Morpholine	A27	120	—
28	Hexanal	Piperidine	A28	120	—
29	Hexanal	Pyrrolidine	A29	120	—
30	Hexanal	Morpholine	A30	120	—

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According to our observations, it is believed that the reaction could be started by the activation of aldehyde using Lewis acid characteristics of BaSiO₃ and subsequently formation of iminium ion intermediate (a) from the reaction of secondary amine with the activated aldehyde. In addition, 4-hydroxycoumarin could be equilibrated with their enolate ion form (b). The final product would be achieved through the reaction of a and b and subsequent keto–enol tautomerization as shown in Scheme 3.

Scheme 3 Proposed mechanism of the reaction for the synthesis of α-benzyl amino coumarin derivatives.

The catalyst recyclability also was investigated in the synthesis of product A₁. In each step, the compound separated from the reaction mixture was washed with acetone and dried at 50 °C. The results of 10 recycling and reuse of the catalyst are shown in Fig. 4. The obtained results show the good recyclability of the catalyst and its good stability. The FT-IR spectrum (Fig. 3) of the recovered catalyst confirms the structural stability of the compound.

Fig. 4 The recyclability test results of BaSiO₃.

Therefore, based on the purpose of this study, efficacy, generality, and the use of barium silicate as an efficient catalyst for the preparation of various α-benzyl amino coumarin derivatives was investigated by using different aromatic aldehydes containing electron-donating or electron-withdrawing groups (Scheme 1). The results are summarized in Table 2.

2.2. In silico ADMET modeling studies

The ADME properties have a significant role in the acceptance or rejection of compounds as potential drug candidates. In addition, toxicity is another property that can damage the organism. Hence, the study of ADMET properties of synthesized compounds before biological evaluation is necessary. The Swiss ADME software was utilized to predict the physiochemical properties of the synthesized compounds (1–24) according to Lipinski and Veber's rules. The molecular weights (MW) of all compounds were in the acceptable range (321–416 g mol⁻¹). The hydrogen bond properties (as donors or acceptors), total polar surface area (TPSA), and the rotatable bond number value of all synthesized compounds were reasonable. Moreover, all of the compounds had admissible lipophilicity (logP) values. Based on these physiochemical properties, all of the α-benzyl amino coumarin derivatives represented good potential for oral bioavailability (Table 3).

Table 3 Physiochemical properties of all α-benzyl amino coumarin derivatives (1–24)

Entry	MW^a	LogP^b	HBD^c	HBA^d	TPSA^e (Å)	RB^f	Lipinski/Veber violation
a Molecular weight (MW).b Logarithm of partition coefficient between n-octanol and water (logP).c Number of hydrogen bond donors (HBD).d Number of hydrogen bond acceptors (HBA).e Topological polar surface area (TPSA).f Number of rotatable bonds (RB).
1	335.4	3.04	1	4	53.68	3	0
2	369.84	3.62	1	4	53.68	3	0
3	369.84	3.52	1	4	53.68	3	0
4	349.42	3.26	1	4	53.68	3	0
5	349.42	3.26	1	4	53.68	3	0
6	365.42	2.69	1	5	62.91	4	0
7	391.50	3.89	1	4	53.68	4	0
8	380.39	2.08	1	6	99.5	4	0
9	404.29	4.01	1	4	53.68	3	0
10	414.29	3.63	1	4	53.68	3	0
11	321.37	2.381	1	4	53.68	3	0
12	400.27	3.41	1	4	53.68	3	0
13	355.81	3.30	1	4	53.68	3	0
14	366.37	1.85	1	6	99.50	4	0
15	335.40	3.04	1	4	53.68	3	0
16	351.40	2.48	1	5	62.91	4	0
17	366.67	1.85	1	6	99.50	4	0
18	337.37	1.93	1	5	62.91	3	0
19	416.27	2.59	1	5	62.91	3	0
20	371.81	2.48	1	5	62.91	3	0
21	382.37	1.06	1	7	108.73	4	0
22	351.40	2.21	1	5	62.91	3	0
23	406.26	2.96	1	5	62.91	3	0
24	402.26	2.96	1	5	62.91	3	0
Lipinski/Veber's rules	≤ 500	≤ 5	≤ 5	≤ 10	≤ 140	≤ 10	≤ 1

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The absorption and distribution properties of the synthesized compounds are displayed in Table 4. The log S value shows the water solubility, which is in the range of −3.63 to −2.18 for all tested compounds. In fact, their lower log S values represented better solubility. The human intestinal absorptions (% HIA) were above 95, which indicated high intestinal absorption in the transport of oral drugs to their biological targets. The Caco-2 permeability of all compounds except analogue 21, illustrated that they exhibit permeability across intestinal membranes. In the case of blood–brain barrier property, compounds 6, 8, 14, 16–17, and 19–22 showed low blood–brain barrier percentages, respectively, leading to a lower neurological effect. Table 4 indicates that all of the tested compounds had no effects on P-glycoprotein efflux transporters as both substrate and inhibitor, therefore, these systems do not disturb the cell permeability and absorption of the compounds. The binding of drug molecules to plasma proteins can affect their bioavailability and distribution across cell membranes. Thus, the percentages of plasma protein binding (PPB) of all compounds was also calculated. All of them had weak PPB with values lower than 90%, except for 3,9, 12, and 19 which showed strong binding to plasma proteins.²⁶

Table 4 Absorption and distribution profile of all α-benzyl amino coumarin compounds^a

Entry	HIA	Caco-2 permeability	BBB	P-Glycoprotein	Plasma protein bonding (PPB)
a NS = non-substrate; NI = non-inhibitor; S = substrate; I = inhibitor.
1	95.89	40.71	0.53	NS/NI	84.19
2	96.35	32.78	1.36	NS/NI	88.44
3	96.35	33.20	1.45	NS/NI	95.61
4	95.99	42.25	1.07	NS/NI	84.00
5	95.99	41.68	1.27	NS/NI	84.18
6	95.94	43.59	0.18	NS/NI	83.07
7	96.28	46.85	3.17	NS/NI	86.23
8	96.85	21.52	0.01	NS/NI	88.55
9	96.73	36.52	3.21	NS/NI	98.25
10	96.04	44.79	1.02	NS/NI	85.61
11	95.79	36.93	0.89	NS/NI	78.15
12	96.55	29.35	0.82	NS/NI	100
13	96.26	30.41	0.72	NS/NI	89.90
14	96.50	16.70	0.01	NS/NI	82.31
15	95.89	38.05	0.60	NS/NI	80.51
16	95.87	40.30	0.10	NS/NI	78.83
17	96.50	21.34	0.01	NS/NI	83.07
18	95.83	37.64	0.60	NS/NI	51.66
19	96.46	29.18	0.15	NS/NI	91.28
20	96.16	30.91	0.14	NS/NI	78.08
21	95.23	9.96	0.01	NS/NI	66.81
22	95.88	38.05	0.07	NS/NI	60.53
23	96.59	33.57	0.27	NS/NI	86.02
24	96.59	33.64	0.50	NS/NI	88.18

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Table 5, illustrates the metabolism and toxicity profiles of all synthesized compounds. Both CYP2D6 and CYP3A4 enzymes have a crucial role in the metabolism of drugs in the liver. In this regard, compounds 1–10 and 21–24 were neither substrates nor inhibitors of CYP2D6 while compounds 11–20 were both substrates and inhibitors of CYP2D6. In the case of CYP3A4 enzymes, none of the compounds were substrates/inhibitors of CYP3A4, except for 14, 16, and 22. The Ames test results represented that compounds 2–3, 6–7, 9–10, 12–13, 19–20, and 23–24 had negative values which indicated their non-mutagenic behavior. All the tested compounds were determined to be non-carcinogenic and, showed lower oral toxicity, so could be considered safe through oral administration. Most of the compounds have weak hERG inhibition, which means that they could not affect QT interval prolongation and cause violent cardiac side effects. Taken together, these results indicate that these synthesized compounds had proper physicochemical and pharmacokinetic properties which would introduce them as ideal candidates for further biological evaluations.

Table 5 Metabolism and toxicity profile of all α-benzyl amino coumarin compounds^a

Entry	CYP2D6	CYP3A4	AMES toxicity	Carcinogenicity	hERG inhibition
a hERG = Human ether-a-go-go related gene, NS = non-substrate; NI = non-inhibitor; S = substrate; I = inhibitor; NC = non-carcinogenic; C = carcinogenic.
1	NS/NI	NS/NI	Toxic	NC	Weak
2	NS/NI	NS/NI	Non toxic	NC	Strong
3	NS/NI	NS/NI	Non toxic	NC	Strong
4	NS/NI	NS/NI	Toxic	NC	Weak
5	NS/NI	NS/NI	Toxic	NC	Weak
6	NS/NI	NS/NI	Non toxic	NC	Weak
7	NS/NI	NS/NI	Non toxic	NC	Weak
8	NS/NI	NS/NI	Toxic	NC	Strong
9	NS/NI	NS/NI	Non toxic	NC	Strong
10	NS/NI	NS/NI	Non toxic	NC	Weak
11	S/I	NS/NI	Toxic	NC	Weak
12	S/I	NS/NI	Non toxic	NC	Weak
13	S/I	NS/NI	Non toxic	NC	Weak
14	S/I	S/I	Toxic	NC	Weak
15	S/I	NS/NI	Toxic	NC	Weak
16	S/I	S/NI	Toxic	NC	Weak
17	S/I	NS/NI	Toxic	NC	Weak
18	S/I	NS/NI	Toxic	NC	Weak
19	S/I	NS/NI	Non toxic	NC	Weak
20	S/I	NS/NI	Non toxic	NC	Weak
21	NS/NI	NS/NI	Toxic	NC	Weak
22	NS/NI	S/I	Toxic	NC	Weak
23	NS/NI	NS/NI	Non toxic	NC	Weak
24	NSN/I	NS/NI	Non toxic	NC	Weak

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3. Experimental

3.1. Reagents and instrumentation

All reagents were purchased from Merck and Aldrich and used without further purification. All yields refer to isolated products after purification. The NMR spectra were recorded on a Bruker Advance DPX 400 MHz instrument. The spectra were measured in DMSO-d6 relative to TMS (0.00 ppm). Elemental analysis was performed on a Heraeus CHN-O-Rapid analyser. TLC was performed on silica gel PolyGram SIL G/UV 254 plates. The powder X-ray diffraction patterns were measured with D8, Advance, Bruker, AXS, and diffractometer using CuKα irradiation. FE-SEM was taken by a Hitachi S-4160 photograph to examine the shape and size of BaSiO₃ nanoparticles.

3.2. Preparation of barium silicate nanopowder

10 ml BaCl₂ and 10 ml tetra ethyl orthosilicate were dissolved in 150 ml ethanol. Then ammonium 18% was added dropwise, while vigorously stirring at room temperature for 24 h. The resultant mixture was aged for 10 h. The gel was dried at 100 °C for 3 h and calcination at 1000 °C for 3 h. The resulting barium silicate was pulverized.²⁵

3.3. General procedure

To a mixture of aldehyde (1.2 mmol), piperidine or other aliphatic amines (1.2 mmol) and 4-hydroxycoumarin (1 mmol) in water (5 ml), BaSiO₃ nanopowder (0.26 mmol) as a catalyst was added and the mixture was stirred for a period of time at room temperature (Table 2). Progress of the reaction was monitored by TLC using n-hexane/ethyl acetate (9 : 1). Upon completion, the solvent was evaporated and the reaction mixture was diluted in hot ethanol. The catalyst was isolated by simple filtration, and the crude product was recrystallized in ethanol/water (75 : 25) to afford the pure product.

3.4. Spectral data

3.4.1. 4-Hydroxy-3-(phenyl(piperidin-1-yl) methyl)-2H-chromen-2-one (A1). Yield: 85% (0.285 mg), white solid, m.p.: 183–185 °C; ¹H-NMR (400 MHz, DMSO-d₆): δ = 1.81–1.91 (m, 6H), 2.24–2.31 (m, 2H), 3.05–3.12 (m, 2H), 5.36 (s, 1H), 7.19 (t, J = 7.6 Hz, 2H), 7.27 (t, J = 7.6 Hz, 1H), 7.34 (d, J = 7.6 Hz, 2H), 7.43 (t, J = 8.2 Hz, 1H), 7.52 (d, J = 8.2 Hz, 1H), 7.80 (t, J = 8.2 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 8.00–8.11 (brs, 1H, OH) ppm; ¹³C-NMR (100 MHz, DMSO-d₆): δ = 22.1, 24.8, 49.6, 71.6, 103.3, 115.3, 119.5, 122.6, 125.3, 127.4, 128.7, 129.7, 130.3, 135.2, 154.5, 162.9, 174.2 ppm; elemental analysis for C₂₁H₂₁NO₃: found: C, 75.12; H, 6.24; N, 4.14%; calculated: C, 75.20; H, 6.31; N, 4.18%.

3.4.2. 3-((2-Chlorophenyl)(piperidin-1-yl)methyl)-4-hydroxy-2H-chromen-2-one (A2). Yield: 87% (0.322 mg), white solid, m.p.: 186–188 °C; ¹H-NMR (400 MHz, DMSO-d₆): δ = 1.80–1.92 (m, 6H), 2.24–2.31 (m, 2H), 3.04–3.12 (m, 2H), 5.48 (s, 1H), 7.22 (t, J = 7.6 Hz, 1H), 7.28 (t, J = 7.8 Hz, 1H), 7.37 (d, J = 7.8 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 7.7 Hz, 1H), 7.79–7.85 (m, 2H), 7.90 (d, J = 8.4 Hz, 1H) ppm; ¹³C-NMR (100 MHz, DMSO-d₆): δ = 22.4, 25.0, 50.41, 74.7, 105.0, 116.1, 120.3, 125.0, 128.6, 129.1, 129.6, 130.1, 130.7, 131.3, 136.1, 144.2, 155.2, 164.4, 174.6 ppm; elemental analysis for C₂₁H₂₀ClNO₃: found: C, 68.26; H, 5.52; N, 3.73%; calculated: C, 68.20; H, 5.45; N, 3.79%.

3.4.3. 3-((4-Chlorophenyl)(piperidin-1-yl)methyl)-4-hydroxy-2H-chromen-2-one (A3). Yield: 70% (0.259 mg), white solid, m.p.: 189–191 °C; ¹H-NMR (400 MHz, DMSO-d₆): δ = 1.82–1.91 (m, 6H), 2.21–2.30 (m, 2H), 3.06–3.12 (m, 2H), 5.48 (s, 1H), 7.24 (d, J = 7.7 Hz, 2H), 7.42–7.54 (m, 5H), 7.81 (t, J = 8.2 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H), ppm; ¹³C-NMR (100 MHz, DMSO-d₆): δ = 21.4, 25.1, 49.7, 73.5, 104.5, 115.4, 120.7, 124.2, 129.3, 130.1, 130.7, 132.8, 135.2, 145.1, 154.7, 164.5, 174.3 ppm; elemental analysis for C₂₁H₂₀ClNO₃: found: C, 68.14; H, 5.53; N, 3.87%; calculated: C, 68.20; H, 5.45; N, 3.79%.

3.4.4. 4-Hydroxy-3-(piperidin-1-yl(o-tolyl) methyl)-2H-chromen-2-one (A4). Yield: 84% (0.293 mg), white solid, m.p.: 201–203 °C; ¹H-NMR (400 MHz, DMSO-d₆): δ = 1.82–1.93 (m, 6H), 2.24–2.30 (m, 2H), 3.07–3.12 (m, 2H), 5.31 (s, 1H), 7.06 (d, J = 7.8 Hz, 1H), 7.12 (t, J = 7.8 Hz, 1H), 7.25–7.30 (m, 2H), 7.42 (t, J = 8.2 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.79 (t, J = 8.1 Hz, 1H), 7.88 (d, J = 8.2 Hz, 1H), 8.10–8.40 (m, 1H, OH) ppm; ¹³C-NMR (100 MHz, DMSO-d₆): δ = 21.1, 21.7, 25.4, 49.6, 73.7, 103.8, 115.1, 120.2, 123.9, 124.5, 126.8, 127.4, 127.8, 130.4, 131.0, 134.0, 137.2, 154.8, 163.9, 173.7 ppm; elemental analysis for C₂₂H₂₃NO₃: found: C, 75.54; H, 6.58; N, 4.11%; calculated: C, 75.62; H, 6.63; N, 4.01%.

3.4.5. 4-Hydroxy-3-(piperidin-1-yl(p-tolyl) methyl)-2H-chromen-2-one (A5). Yield: 81% (0.282 mg), white solid, m.p.: 197–199 °C; ¹H-NMR (400 MHz, DMSO-d₆): δ = 1.78–1.89 (m, 6H), 2.20–2.27 (m, 2H), 2.31 (s, 3H), 3.06–3.13 (m, 2H), 5.14 (s, 1H), 7.24 (d, J = 7.7 Hz, 2H), 7.42–7.54 (m, 5H), 7.81 (t, J = 8.2 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.13 (d, J = 7.7 Hz, 2H), 7.24 (d, J = 7.7 Hz, 2H), 7.42 (t, J = 8.4 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.79 (t, J = 8.2 Hz, 1H), 7.88 (d, J = 8.2 Hz, 1H) ppm; ¹³C-NMR (100 MHz, DMSO-d₆): δ = 21.5, 22.4, 25.6, 49.9, 73.5, 103.9, 115.4, 120.1, 121.8, 124.5, 127.8, 130.4, 131.0, 134.0, 137.7, 154.7, 163.6, 173.9 ppm; elemental analysis for C₂₂H₂₃NO₃: found: C, 75.66; H, 6.72; N, 4.08%; calculated: C, 75.62; H, 6.63; N, 4.01%.

3.4.6. 4-Hydroxy-3-((4-methoxyphenyl)(piperidin-1-yl)methyl)-2H-chromen-2-one (A6). Yield: 70% (0.256 mg), white solid, m.p.: 192–194 °C; ¹H-NMR (400 MHz, DMSO-d₆): δ = 1.79–1.86 (m, 6H), 2.22–2.27 (m, 2H), 3.08–3.11 (m, 2H), 3.79 (s, 3H), 4.09 (s, 1H), 6.96 (d, J = 7.7 Hz, 2H), 7.12 (d, J = 7.7 Hz, 2H), 7.42 (t, J = 8.4 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.79 (t, J = 8.2 Hz, 1H), 7.88 (d, J = 8.2 Hz, 1H) ppm; ¹³C-NMR (100 MHz, DMSO-d₆): δ = 21.6, 25.5, 50.1, 56.1, 73.4, 103.7, 115.6, 117.2, 121.6, 124.1, 124.2, 129.1, 130.1, 131.0, 154.6, 156.2, 163.4, 173.1 ppm; elemental analysis for C₂₂H₂₃NO₄: found: C, C, 72.37; H, 6.39; N, 3.89%; calculated: C, 72.31; H, 6.34; N, 3.83%.

3.4.7. 3-((4-(tert-Butyl)phenyl)(piperidin-1-yl)methyl)-4-hydroxy-2H-chromen-2-one (A7). Yield: 89% (0.348 mg), white solid, m.p.: 207–209 °C; ¹H-NMR (400 MHz, DMSO-d₆): δ = 1.29 (s, 9H), 1.82–1.89 (m, 6H), 2.23–2.26 (m, 2H), 3.04–3.09 (m, 2H), 5.29 (s, 1H), 7.14 (d, J = 7.7 Hz, 2H), 7.25 (d, J = 7.7 Hz, 2H), 7.43 (t, J = 8.4 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.80 (t, J = 8.2 Hz, 1H), 7.89 (d, J = 8.2 Hz, 1H), ppm; ¹³C-NMR (100 MHz, DMSO-d₆): δ = 14.8, 21.4, 25.5, 34.3, 50.3, 73.6, 103.4, 115.4, 121.6, 124.7, 126.7, 127.9, 130.2, 131.2, 133.5, 138.2, 154.5, 163.1, 173.5 ppm; elemental analysis for C₂₅H₂₉NO₃: found: C, 76.77; H, 7.53; N, 3.51%; calculated: C, 76.70; H, 7.47; N, 3.58%.

3.4.8. 4-Hydroxy-3-((3-nitrophenyl)(piperidin-1-yl) methyl)-2H-chromen-2-one (A₈). Yield: 90% (0.342 mg), yellow solid, m.p.: 218–220 °C; ¹H-NMR (400 MHz, DMSO-d₆): δ = 1.83–1.92 (m, 6H), 2.25–2.29 (m, 2H), 3.08–3.13 (m, 2H), 5.72 (s, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.80 (t, J = 8.0 Hz, 1H), 7.91 (d, J = 8.1 Hz, 1H), 8.27 (d, J = 7.8 Hz, 1H), 8.02 (d, J = 7.8 Hz, 1H), 8.49 (s, 1H), 8.50–8.90 (m, 1H, OH) ppm; ¹³C-NMR (100 MHz, DMSO-d₆): δ = 21.9, 25.7, 50.5, 75.6, 103.7, 115.9, 121.7, 124.8, 128.7, 129.1, 129.6, 130.1, 130.9, 131.4, 134.5, 139.2, 154.7, 164.1, 175.5 ppm; elemental analysis for C₂₁H₂₀N₂O₅: found: C, 66.26; H, 5.25; N, 7.31%; calculated: C, 66.31; H, 5.30; N, 7.36%.

3.4.9. 3-((2,4-Dichlorophenyl)(piperidin-1-yl)methyl)-4-hydroxy-2H-chromen-2-one (A₉). Yield: 61% (0.246 mg), white solid, m.p.: 211–213 °C; ¹H-NMR (400 MHz, DMSO-d₆): δ = 1.84–1.90 (m, 6H), 2.25–2.28 (m, 2H), 3.08–3.12 (m, 2H), 5.52 (s, 1H), 7.41–7.51 (m, 3H), 7.69 (d, J = 7.8 Hz, 1H), 7.77–7.81 (m, 2H), 7.88 (d, J = 8.3 Hz, 1H) 7.95–8.30 (m, 1H, OH) ppm; ¹³C-NMR (100 MHz, DMSO-d₆): δ = 21.7, 25.8, 50.3, 74.3, 103.5, 115.7, 122.0, 124.6, 127.7, 128.9, 129.3, 130.2, 131.4, 134.1, 141.2, 143.6, 154.6, 163.9, 174.5 ppm; elemental analysis for C₂₁H₁₉Cl₂NO₃: found: C, 62.39; H, 4.74; N, 3.46%; calculated: C, 62.39; H, 4.74; N, 3.46%.

3.4.10. 3-((4-Bromophenyl)(piperidin-1-yl)methyl)-4-hydroxy-2H-chromen-2-one (A₁₀). Yield: 90% (0.373 mg), white solid, m.p.: 203–205 °C; ¹H-NMR (400 MHz, DMSO-d₆): δ = 1.78–1.88 (m, 6H), 2.22–2.28 (m, 2H), 3.08–3.14 (m, 2H), 5.59 (s, 1H), 7.39–7.52 (m, 5H), 7.75–7.89 (m, 5H) ppm; ¹³C-NMR (100 MHz, DMSO-d₆): δ = 21.7, 25.4, 49.8, 73.9, 103.5, 115.1, 121.6, 124.3, 128.9, 130.2, 131.3, 132.9, 133.7, 148.3, 154.7, 163.9, 174.7 ppm; elemental analysis for C₂₁H₂₀BrNO₃: found: C, 60.85; H, 4.82; N, 3.31%; calculated: C, 60.88; H, 4.87; N, 3.38%.

3.4.11. 4-Hydroxy-3-(phenyl(pyrrolidin-1-yl) methyl)-2H-chromen-2-one (A11). Yield: 82% (0.264 mg), white solid, m.p.: 167–169 °C; ¹H-NMR (400 MHz, DMSO-d₆): δ = 2.02–2.10 (m, 4H), 3.02–3.08 (m, 2H), 3.41–3.47 (m, 2H), 5.19 (s, 1H), 7.19–7.33 (m, 5H), 7.41 (t, J = 8.4 Hz, 1H), 7.49 (d, J = 8.2 Hz, 1H), 7.69 (t, J = 8.3 Hz, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.99 (brs, 1H, OH) ppm; ¹³C-NMR (100 MHz, DMSO-d₆): δ = 26.7, 53.6, 72.3, 103.5, 115.7, 120.1, 123.6, 125.7, 127.8, 128.6, 129.5, 130.3, 134.9, 154.7, 163.1, 173.9 ppm; elemental analysis for C₂₀H₁₉NO₃: found: C, 74.69; H, 5.99; N, 4.42; calculated: C, 74.75; H, 5.96; N, 4.36%.

3.4.12. 3-((4-Bromophenyl) (pyrrolidin-1-yl)methyl)-4-hydroxy-2H-chromen-2-one (A12). Yield: 90% (0.360 mg), white solid, m.p.: 188–190 °C; ¹H-NMR (400 MHz, DMSO-d₆): δ = 2.04–2.11 (m, 4H), 3.01–3.06 (m, 2H), 3.41–3.43 (m, 2H), 5.39 (s, 1H), 7.35 (d, J = 7.7 Hz, 2H), 7.40 (t, J = 8.4 Hz, 1H), 7.48 (d, J = 8.2 Hz, 1H), 7.65 (d, J = 7.7 Hz, 2H), 7.67 (t, J = 8.3 Hz, 1H), 7.90 (d, J = 8.2 Hz, 1H), 7.96 (brs, 1H, OH) ppm; ¹³C-NMR (100 MHz, DMSO-d₆): δ = 26.4, 53.6, 74.2, 103.7, 115.1, 121.6, 124.5, 128.8, 130.2, 131.2, 133.3, 134.6, 148.1, 154.7, 164.1, 174.8 ppm; elemental analysis for C₂₀H₁₈BrNO₃: found: C, 60.08; H, 4.59; N, 3.55; calculated: C, 60.01; H, 4.53; N, 3.50%.

3.4.13. 3-((4-Chlorophenyl) (pyrrolidin-1-yl)methyl)-4-hydroxy-2H-chromen-2-one (A13). Yield: 93% (0.331 mg), white solid, m.p.: 175–177 °C; ¹H-NMR (400 MHz, DMSO-d₆): δ = 2.04–2.12 (m, 4H), 3.00–3.06 (m, 2H), 3.40–3.46 (m, 2H), 5.46 (s, 1H), 7.27 (d, J = 7.7 Hz, 2H), 7.41 (t, J = 8.4 Hz, 1H), 7.48 (d, J = 7.7 Hz, 2H), 7.52 (d, J = 8.4 Hz, 1H), 7.67 (brs, 1H, OH), 7.80 (t, J = 8.2 Hz, 1H), 7.90 (d, J = 8.2 Hz, 1H) ppm; ¹³C-NMR (100 MHz, DMSO-d₆): δ = 26.4, 52.8, 74.1, 105.9, 115.8, 121.2, 124.6, 129.8, 130.1, 131.3, 132.8, 135.1, 144.5, 154.7, 164.1, 174.8 ppm; elemental analysis for C₂₀H₁₈ClNO₃: found: C, 67.44; H, 5.02; N, 3.85; calculated: C, 67.51; H, 5.10; N, 3.94%.

3.4.14. 4-Hydroxy-3-((4-nitrophenyl) (pyrrolidin-1-yl) methyl)-2H-chromen-2-one (A14). Yield: 88% (0.322 mg), yellow solid, m.p.: 193–195 °C; ¹H-NMR (400 MHz, DMSO-d₆): δ = 2.06–2.12 (m, 4H), 3.04–3.07 (m, 2H), 3.44–3.47 (m, 2H), 5.76 (s, 1H), 7.42 (t, J = 8.3 Hz, 1H), 7.52 (d, J = 8.3 Hz, 1H), 7.77 (d, J = 7.9 Hz, 2H), 7.81 (t, J = 8.3 Hz, 1H), 7.91 (d, J = 8.3 Hz, 1H), 7.90–8.20 (brs, 1H, OH), 8.28 (d, J = 7.8 Hz, 2H) ppm; ¹³C-NMR (100 MHz, DMSO-d₆): δ = 26.4, 53.4, 77.4, 106.1, 116.0, 121.2, 124.6, 130.2, 130.6, 131.4, 134.1, 137.1, 139.5, 154.8, 164.6, 175.6 ppm; elemental analysis for C₂₀H₁₈N₂O₅: found: C, 65.66; H, 4.99; N, 7.61; calculated: C, 65.57; H, 4.95; N, 7.65%.

3.4.15. 4-Hydroxy-3-(pyrrolidin-1-yl(p-tolyl)methyl)-2H-chromen-2-one (A15). Yield: 89% (0.299 mg), white solid, m.p.: 176–178 °C; ¹H-NMR (400 MHz, DMSO-d₆): δ = 2.01–2.09 (m, 4H), 2.28 (s, 3H), 3.01–3.05 (m, 2H), 3.41–3.45 (m, 2H), 5.16 (s, 1H), 7.01 (d, J = 7.7 Hz, 2H), 7.21 (d, J = 7.7 Hz, 2H), 7.40 (t, J = 8.4 Hz, 1H), 7.48 (d, J = 8.2 Hz, 1H), 7.69 (t, J = 8.3 Hz, 1H), 7.89–7.94 (m, 3H) ppm; ¹³C-NMR (100 MHz, DMSO-d₆): δ = 21.6, 26.1, 51.2, 73.1, 104.8, 115.2, 120.1, 121.6, 124.7, 128.2, 130.2, 131.3, 134.1, 137.8, 154.5, 163.3, 173.2 ppm; elemental analysis for C₂₁H₂₁NO₃: found: C, 75.14; H, 6.27; N, 4.13; calculated: C, 75.20; H, 6.31; N, 4.18%.

3.4.16. 4-Hydroxy-3-((4-methoxyphenyl) (pyrrolidin-1-yl) methyl)-2H-chromen-2-one (A16). Yield: 95% (0.334 mg), white solid, m.p.: 174–176 °C; ¹H-NMR (400 MHz, DMSO-d₆): δ = 2.02–2.09 (m, 4H), 3.01–3.05 (m, 2H), 3.41–3.45 (m, 2H), 3.73 (s, 3H), 5.16 (s, 1H), 6.91 (d, J = 7.7 Hz, 2H), 7.07 (d, J = 7.7 Hz, 2H), 7.40 (t, J = 8.4 Hz, 1H), 7.48 (d, J = 8.2 Hz, 1H), 7.67–7.71 (m, 2H), 7.92 (d, J = 8.2 Hz, 1H) ppm; ¹³C-NMR (100 MHz, DMSO-d₆): δ = 26.5, 51.1, 56.7, 73.1, 103.5, 115.8, 117.5, 121.4, 124.3, 124.8, 129.0, 130.3, 131.2, 154.6, 156.4, 163.6, 171.4 ppm; elemental analysis for C₂₁H₂₁NO₄: found: C, 71.74; H, 5.98; N, 3.95; calculated: C, 71.78; H, 6.02; N, 3.99%.

3.4.17. 4-Hydroxy-3-((3-nitrophenyl)(pyrrolidin-1-yl)methyl)-2H-chromen-2-one (A17). Yield: 92% (0.337 mg), yellow solid, m.p.: 195–197 °C; ¹H-NMR (400 MHz, DMSO-d₆): δ = 2.02–2.12 (m, 4H), 3.01–3.08 (m, 2H), 3.38–3.45 (m, 2H), 5.79 (s, 1H), 7.43 (t, J = 8.1 Hz, 1H), 7.52 (d, J = 8.1 Hz, 1H), 7.55 (t, J = 7.8 Hz, 1H), 7.78 (t, J = 8.2 Hz, 1H), 7.90 (d, J = 8.2 Hz, 1H), 7.98 (d, J = 7.8 Hz, 1H), 8.25 (d, J = 7.8 Hz, 1H), 8.47 (s, 1H), 9.40–9.70 (brs, 1H, OH) ppm; ¹³C-NMR (100 MHz, DMSO-d₆): δ = 26.7, 51.8, 77.3, 104.1, 116.1, 121.5, 124.6, 128.9, 129.4, 129.9, 130.2, 131.2, 131.6, 135.3, 139.7, 154.6, 164.3, 176.4 ppm; elemental analysis for C₂₀H₁₈N₂O₅: found: C, 65.64; H, 5.03; N, 7.63; calculated: C, 65.57; H, 4.95; N, 7.65%.

3.4.18. 4-Hydroxy-3-(morpholino(phenyl)methyl)-2H-chromen-2-one (A18). Yield: 93% (0.314 mg), white solid, m.p.: 172–174 °C; ¹H-NMR (400 MHz, DMSO-d₆): δ = 2.95–3.01 (m, 2H), 3.29–3.35 (m, 2H), 3.73–3.92 (m, 4H), 5.34 (s, 1H), 7.19–7.33 (m, 6H), 7.45 (t, J = 8.2 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.82 (t, J = 8.2 Hz, 1H), 7.90 (d, J = 8.2 Hz, 1H) ppm; ¹³C-NMR (100 MHz, DMSO-d₆): δ = 59.8, 64.6, 74.6, 104.4, 116.2, 120.7, 123.6, 125.7, 127.6, 128.7, 129.6130.4, 136.4, 155.2, 163.9, 174.6 ppm; elemental analysis for C₂₀H₁₉NO₄: found: C, 71.26; H, 5.74; N, 4.08; calculated: C, 71.20; H, 5.68; N, 4.15%.

3.4.19. 3-((4-Bromophenyl)(morpholino)methyl)-4-hydroxy-2H-chromen-2-one (A19). Yield: 90% (0.375 mg), white solid, m.p.: 189–191 °C; ¹H-NMR (400 MHz, DMSO-d₆): δ = 2.96–3.02 (m, 2H), 3.31–3.95 (m, 6H), 5.44 (s, 1H), 7.32 (d, J = 7.7 Hz, 2H), 7.42–7.56 (m, 5H), 7.82 (t, J = 8.2 Hz, 1H), 7.91 (d, J = 8.2 Hz, 1H) ppm; ¹³C-NMR (100 MHz, DMSO-d₆): δ = 60.4, 66.6, 78.2, 104.7, 116.1, 121.6, 124.4, 128.9, 130.2, 131.1, 133.4, 135.6, 148.4, 155.2, 164.3, 174.1 ppm; elemental analysis for C₂₀H₁₈BrNO₄: found: C, 57.75; H, 4.44; N, 3.42; calculated: C, 57.71; H, 4.36; N, 3.36%.

3.4.20. 3-((4-Chlorophenyl)(morpholino)methyl)-4-hydroxy-2H-chromen-2-one (A20). Yield: 98% (0.364 mg), white solid, m.p.: 171–173 °C; ¹H NMR (400 MHz, DMSO-d₆): δ = 2.94–3.97 (m, 8H), 5.67 (s, 1H), 7.26 (d, J = 7.8 Hz, 2H), 7.41–7.53 (m, 4H), 7.78 (t, J = 8.3 Hz, 1H), 7.90 (d, J = 8.3 Hz, 1H), 7.90–8.00 (brs, 1H, OH) ppm; ¹³C-NMR (100 MHz, DMSO-d₆): δ = 60.1, 66.4, 76.7, 104.5, 116.0, 121.6, 124.3, 127.8, 129.6, 130.1, 131.3, 134.8, 142.4, 155.3, 164.1, 172.1 ppm; elemental analysis for C₂₀H₁₈ClNO₄: found: C, 64.53; H, 4.79; N, 3.81; calculated: C, 64.61; H, 4.88; N, 3.77%.

3.4.21. 4-Hydroxy-3-(morpholino(4-nitrophenyl) methyl)-2H-chromen-2-one (A21). Yield: 78% (0.298 mg), yellow solid, m.p.: 185–187 °C; ¹H-NMR (400 MHz, DMSO-d₆): δ = 2.96–3.94 (m, 8H), 6.39 (s, 1H), 7.42 (t, J = 8.4 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.67 (t, J = 8.4 Hz, 1H), 7.78 (d, J = 7.7 Hz, 2H), 7.94 (d, J = 8.4 Hz, 1H), 8.03 (d, J = 7.7 Hz, 2H), 7.90–8.00 (brs, 1H, OH) ppm; ¹³C-NMR (100 MHz, DMSO-d₆): δ = 61.2, 68.3, 82.4, 106.3, 116.4, 121.3, 124.6, 129.3, 130.4, 131.3, 132.4, 137.3, 140.1, 155.2, 164.8, 178.9 ppm; elemental analysis for C₂₀H₁₈N₂O₄: found: C, 62.73; H, 4.71; N, 7.28%; calculated: C, 62.82; H, 4.75; N, 7.33%.

3.4.22. 4-Hydroxy-3-(morpholino(p-tolyl) methyl)-2H-chromen-2-one (A22). Yield: 90% (0.316 mg), white solid, m.p.: 173–175 °C; ¹H-NMR (400 MHz, DMSO-d₆): δ = 2.94–3.97 (m, 8H), 5.48 (s, 1H), 7.14 (d, J = 7.8 Hz, 2H), 7.26 (d, J = 7.8 Hz, 2H), 7.42 (t, J = 8.3 Hz, 1H), 7.51 (d, J = 8.3 Hz, 1H), 7.77 (t, J = 8.3 Hz, 1H), 7.89 (d, J = 8.3 Hz, 1H), 7.95–8.10 (brs, 1H, OH) ppm; ¹³C-NMR (100 MHz, DMSO-d₆): δ = 21.5, 59.7, 65.8, 74.2, 104.9, 115.4, 120.2, 121.6, 124.7, 128.6, 130.1, 131.4, 134.0, 137.7, 154.5, 163.7, 174.2 ppm; elemental analysis for C₂₁H₂₁NO₄: found: C, 71.71; H, 6.09; N, 4.06%; calculated: C, 71.78; H, 6.02; N, 3.99%.

3.4.23. 3-((2,4-Dichlorophenyl)(morpholino)methyl)-4-hydroxy-2H-chromen-2-one (A23). Yield: 92% (0.374 mg), white solid, m.p.: 193–195 °C; ¹H-NMR (400 MHz, DMSO-d₆): δ = 2.95–3.99 (m, 8H), 5.82 (s, 1H), 7.41–7.46 (m, 3H), 7.50 (d, J = 8.3 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.79 (t, J = 8.2 Hz, 1H), 7.81 (s, 1H), 7.88 (d, J = 8.3 Hz, 1H), 7.94–8.25 (brs, 1H, OH) ppm; ¹³C-NMR (100 MHz, DMSO-d₆): δ = 60.3, 66.4, 76.9, 105.1, 115.6, 121.7, 124.7, 128.8, 129.2, 130.1, 131.3, 132.3, 135.4, 143.7, 145.6, 154.8, 164.1, 177.2 ppm; elemental analysis for C₂₀H₁₇Cl₂NO₄: found: C, 59.01; H, 4.15; N, 3.33%; calculated: C, 59.13; H, 4.22; N, 3.45%.

3.4.24. 3-((3,5-Dichlorophenyl)(morpholino)methyl)-4-hydroxy-2H-chromen-2-one (A24). Yield: 89% (0.362 mg), white solid, m.p.: 196–198 °C;¹H-NMR (400 MHz, DMSO-d₆): δ = 2.94–3.98 (m, 8H), 5.80 (s, 1H), 7.42 (t, J = 8.4 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.75–7.90 (m, 5H), 8.11 (s, 1H) ppm; ¹³C-NMR (100 MHz, DMSO-d₆): δ = 60.3, 66.7, 75.7, 105.0, 115.7, 121.4, 124.3, 129.8, 130.1, 131.4, 133.3, 134.8, 142.7, 155.0, 164.3, 176.6 ppm; elemental analysis for C₂₀H₁₇Cl₂NO₄: found: C, 59.34; H, 4.28; N, 3.36%; calculated: C, 59.13; H, 4.22; N, 3.45%.

3.5. In silico physicochemical parameters and ADMET profiling calculations

The physicochemical properties and drug-likeness studies of all α-benzyl amino coumarin compounds were obtained and evaluated for ADMET characteristics under Lipinski's rule of five and Veber rules by using SwissADME online software, the preADMET online server (https://preadmet.webservice.bmdrc.org/) and admetSAR (http://lmmd.ecust.edu.cn/admetsar2/) online server.

4. Conclusion

In summary, we have demonstrated an elegant and environmentally friendly protocol for the synthesis of α-benzyl amino coumarin derivatives by using barium silicate nanoparticles as a catalyst and water as a green solvent. Compared with other methods in existence, our method provides the advantages of better yields, inexpensive operation, cleaner reaction profile, and environmental friendliness. The in silico ADMET analysis performed within this study indicated that all synthesized compounds are in agreement with Lipinski's and Veber's rules. Also, the results of toxicity risk assessment tests showed that none of the compounds exhibit a risk of mutagenicity, tumorigenicity, irritation, or acute oral toxicity which highlights their potential as ideal chemotherapeutic agents.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We are thankful to the Najafabad Branch, Islamic Azad University research council, and Shiraz University of Medical Sciences grant number 24994, for partial support of this research.

References

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Footnote

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d3ra00796k

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