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Abstract

Objective: The study was conducted to evaluate the in vitro acetylcholinesterase (AchE) inhibition activity of novel pyrano[2,3-d]pyrimidine derivatives. Methods: A series of new pyrano[2,3-d]pyrimidine derivatives were synthesized in moderate to good yields (63%-81%) by using microwave-prompted “one-pot” two-step multicomponent reactions of cyclohexane-1,3-dione, malononitrile, aldehydes, and acetic anhydride. Noticeably, Diazabicyclo[2.2.2]octane was successfully employed as a basic catalyst for the formation of 2-amino-4H-pyran-3-carbonitrile intermediates. These products were identified using spectral data, and assessed in terms of their AChE inhibition activity and cytotoxicity against three types of human cancer cell lines including epidermoid carcinoma (KB), hepatoma carcinoma (HepG2), and non-small lung cancer (A549) cell lines. Results: Most of the products depicted moderate to good AChE inhibitory activity, among them, one product with methoxy moiety at meta-position on phenyl group showed the best AchE inhibition activity with IC₅₀ values of 2.20 ± 0.17 µg/mL. Moreover, products exhibited no cytotoxicity against cancer cell lines. Conclusion: This study highlighted that pyrano[2,3-d]pyrimidine derivatives as promising candidates for further investigations directed to the discovery of new AChE inhibitors which could be used in Alzheimer's disease therapy.

Keywords

AChE inhibitors Alzheimer's disease cytotoxicity multicomponent reaction pyrano[2 3-d]pyrimidine

Introduction

Alzheimer's disease (AD), an age-related neurodegenerative disease, is characterized by memory loss, decline in language, and a cognitive and behavioral disorders.¹ AD is one of the most dangerous diseases, ranking fifth in terms of mortality rate among adults aged 65 and older, as well as seventh in mortality rate among all adults in 2020 and 2021.² Studies demonstrated that many factors are involved in the pathophysiology of AD. For example, there is a deficient cholinergic neurotransmission function,³ accumulation of aggregates of amyloid-β (Aβ)⁴ and hyperphosphorylated tau proteins,⁵ increased production of reactive oxygen species (ROS),⁶ imbalance of biometals (zinc, copper, calcium, and iron) in the brain,⁷ and deficits in acetylcholine (ACh).⁸ Acetylcholinesterase (AChE), a form of cholinesterases, is known to immediately hydrolyze ACh in cholinergic synapses and stimulate the aggregation of amyloid-β peptide fragments and thus contributing to amyloid formation.⁹ Therefore, common therapeutic treatments for AD have been mainly based on enhancing cholinergic function by utilizing AchE inhibitors (AChEIs) to improve the levels of acetylcholine (ACh) in cholinergic synapses.¹⁰ Up to now, the FDA has approved four AChEIs (donepezil, tacrine, galantamine, and rivastigmine), an N-methyl-D-aspartic acid (NMDA) antagonist (memantine), and a humanized IgG1 monoclonal antibody (lecanemab) for the treatment of AD.^11,12 However, the increasing use of AChEIs has led to reduced AChEIs efficacy, increased adverse drug reactions (ADRs), and serious side effects.^13–15 Accordingly, the pursuit of new AChE inhibitors with fewer side effects has attracted great interest among scientists.^16–19

In this regard, pyrimidine, a N-based heterocyclic ring, is a privileged substructural motif in a diversity of drugs/lead, including antimicrobial,²⁰ antibacterial,²¹ antitumor,²² anticancer,²³ cytotoxicity,²⁴ HMG-CoA reductase inhibitors,²⁵ and more. Notably, a novel series of pyrimidine-based molecules have been developed with roles as potential treatments for AD, functioning as γ-secretase modulators, cholinesterase inhibitors, Aβ aggregation inhibitors, and BACE1 (β-secretase) inhibitors.^26–29 For example, Rao et al have reported pyrido[3,2-d]pyrimidine bioisostere 1 as a promising multitargeting agent in Alzheimer’s disease, exhibiting good anti-Aβ activity (Aβ40 IC₅₀ = 1.1 µM), dual ChE inhibition (AChE IC₅₀ = 7.8 µM and BuChE IC₅₀ = 29.3 µM), and iron-chelating properties (23.6% chelation at 50 µM).²⁸ In our previous study, a group of triazole-pyrimidine hybrids was developed, and compound 2 (Figure 1) was identified as a lead compound based on its AChE inhibition profile (IC₅₀ (AChE) = 0.23 µM).²⁹ Apart from pyrimidine, pyran, an oxygen-containing heterocyclic moiety, is an integral part of significant natural compounds, such as polyether antibiotics, carbohydrates, pheromones, alkaloids, and iridoids.³⁰ These compounds have also played key roles in providing a variety of bioactive molecules with activities including anticancer,³¹ antitumor,³² antiallergic,³³ anti-HIV,³⁴ antibacterial,³⁵ antifungal,³⁶ antimicrobial,³⁷ antioxidant,³⁸ antimalarial,^39,40 spasmolytic,⁴¹ and the inhibition of calcium signaling.⁴² Nowadays, the design and synthesis of furan-fused heterocycles have proven to be highly attractive and useful for developing new potent drug molecules.^43–47 The promising activities of pyrimidines and pyran-fused heterocycles have encouraged us to design and synthesize new pyrano[2,3-d]pyrimidines with the aim of identifying new lead compounds for use in AD therapy.

Figure 1.

Structure of potent multi-targeting agents in Alzheimer's disease.^28,29.

A number of reports have appeared in the literature regarding the multicomponent synthesis of pyrano[2,3-d]pyrimidines, which are unsaturated six-membered heterocycles formed by fusion of pyran and pyrimidine rings.^48–52 Nevertheless, less works have employed the 2-amino-4H-pyran-3-carbonitrile derivatives to construct pyrano[2,3-d]pyrimidines skeleton directly. Furthermore, numerous effective synthetic methods have been recorded for generating 2-amino-4H-pyran-3-carbonitrile intermediates.^53–62 Therefore, as part of our ongoing research focused on the discovery of novel bioactive compounds,^63–67 in this study, we focused on the synthesis and biological evaluation of novel pyrano[2,3-d]pyrimidine compounds 8a-k. The newly synthesized molecules were evaluated for their AChE inhibitory activity, along with an evaluation of their cytotoxicity, to investigate their potential for use in treating AD.

Results and Discussion

Nowadays, organocatalysts have been used extensively in green chemistry and small molecule drug discovery because of their efficiency, stability, purity, and selectivity.⁶⁸ Diazabicyclo[2.2.2]octane (DABCO), an organocatalyst, has received considerable attention as an inexpensive, eco-friendly, highly reactive, and nontoxic base catalyst in the synthesis of pyran derivatives through multicomponent reactions.^69,70 In our previous study, utilizing DABCO as a base catalyst and acetonitrile as a solvent, we successfully synthesized 2-amino-5,10-dioxo-4-aryl-5,10-dihydro-4H-benzo[g]chromene-3-carbonitrile compounds in good yields via the microwave-assisted three-component reaction of 1,4-naphthoquinone, malononitrile, and various arylaldehydes.⁴⁹ Therefore, in this study, 0.2 mmol of DABCO as a base catalyst was added to the mixture of cyclohexane-1,3-dione (1 mmol), malononitrile (1 mmol), and 4-methoxyaldehyde (1 mmol) in acetonitrile. The reaction mixture was stirred at 82 °C in 15 min under microwave irradiation to furnish 2-amino-4-(4-methoxyphenyl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (6a). After purification steps, intermediate 6a was obtained in high yield (89%) and determined by IR, ¹H NMR ¹³C NMR spectra. IR spectrum of this compound revealed the presence of CN bond at 2186 cm⁻¹, N-H bond (primary amine) at 3460-3300 cm⁻¹, and 1601 cm⁻¹. Accordingly, 2-amino-4H-pyran-3-carbonitrile intermediates 6 were synthesized under identical conditions, and subsequently transformed into pyrano[2,3-d]pyrimidine without undergoing purification steps. Transformation of intermediates 6 into pyrano[2,3-d]pyrimidines 8a-k upon the treatment with 3 mmol of acetic anhydride (7) at 120 °C for 15 min in the presence of 0.4 mmol of concentrated sulfuric acid. As shown in Scheme 1, aldehydes bearing either electron-withdrawing groups (nitro, halogen) or electron-donating groups (methyl, methoxy) at different positions furnished good yields (73%-81%) of products 8a-i. Heterocyclic aldehydes seemed to deliver products 8j, k in lower yields (63%-67%). The products 8a-k were identified by IR, ¹H NMR, ¹³C NMR, and HRMS.

Scheme 1.

Synthesis of pyrano[2,3-d]pyrimidine compounds 8a-k.

The plausible mechanism for the formation of products 8 was described in Scheme 2. The 2-amino-4H-pyran-3-carbonitrile intermediates 6 were prepared in the presence of DABCO as a base catalyst. Initially, the Knoevenagel condensation of cyclohexane-1,3-dione (3) with aldehyde 4, followed by dehydration, and the Michael addition, generated intermediates 12, which gave rise to intermediates 6 upon intramolecular cyclization and [1,3]-hydrogen shift. After that, a nucleophilic addition-elimination reaction between intermediates 6 and acetic anhydride (7), followed by a cyan-hydrolysis afforded intermediates 17. These intermediates then underwent intramolecular cyclization and dehydration to generate products 8.

Scheme 2.

The plausible reaction mechanism.

The ability of pyrano[2,3-d]pyrimidines to inhibit the AChE enzymes was then evaluated by the modified Ellman's method.²⁹ AChE inhibitory activity results were expressed as inhibitory concentration 50% (IC₅₀, µg/mL) and donepezil was used as a reference. As shown in Table 1, while products 8g (Ar = 2-NO₂C₆H₄) and 8k (Ar = benzo[b]thiophen-3-yl) exhibited no inhibitory activity toward AChE with IC₅₀ > 32 µg/mL, other products offered moderate to good inhibitory activity toward AChE with IC₅₀ values ranging from 2.20 to 13.79 µg/mL. Among them, product 8i (Ar = 3-CH₃OC₆H₄) displayed the strongest AChE inhibitory activity (IC₅₀ = 2.20 ± 0.17 µg/mL). In terms of structure–activity relationship, it seems that the AChE enzyme inhibitory potency of products was mainly affected by substituents on the phenyl ring attached to pyran ring. Generally, products possessing halogen substituents (bromo, trifluoromethyl, chloro groups) on the phenyl ring exhibited good inhibition. For instance, products 8c with a bromo group at para-position and 8f with a bromo group at meta-position exhibited AChEI activity with IC₅₀ values of 3.45 ± 0.28 and 3.21 ± 0.34 µg/mL, respectively. Interestingly, changing the bromo group to meta-position instead of para-position led to a slight increase in the activity. This demonstrated that meta-position directly contributed to the higher inhibitory activity. Further support for this hypothesis may be provided by the observation of improved AChEI activity in the case of products 8i and 8h. The inhibitory activity toward AChE was further enhanced in product 8i (IC₅₀ = 2.20 ± 0.17 µg/mL), where a phenyl ring possesses a methoxy at meta-position, as compared to products 8a possessing a methoxy at para-position (IC₅₀ = 13.79 ± 1.24 µg/mL). In particular, introducing a nitro group at meta-position, as seen in product 8h (IC₅₀ = 8.00 ± 0.84 µg/mL), resulted in a fairly good inhibitory activity, while the same group at ortho-position made product 8g inactive. Besides that, it is worthwhile to notice that products containing aryl groups seem to depict higher activities than heteroaryl groups.

Table 1.

Inhibitory Activity of Pyrano[2,3-d]Pyrimidine Derivatives (8a-k) Against AChE and Their Cytotoxic Activity Against Different Cancer Cell Lines.

Entry	Compound	Ar	IC₅₀ (µg/mL)
Entry	Compound	Ar	AChE	KB	HepG2	A549
1	8a	4-CH₃OC₆H₄	13.79 ± 1.24	> 32	> 32	> 32
2	8b	4-CH₃C₆H₄	7.04 ± 0.63	> 32	> 32	> 32
3	8c	4-BrC₆H₄	3.45 ± 0.28	> 32	> 32	> 32
4	8d	4-CF₃C₆H₄	3.04 ± 0.37	> 32	> 32	> 32
5	8e	4-ClC₆H₄	8.00 ± 0.89	> 32	> 32	> 32
6	8f	3-BrC₆H₄	3.21 ± 0.34	> 32	> 32	> 32
7	8g	2-NO₂C₆H₄	>32	> 32	> 32	> 32
8	8h	3-NO₂C₆H₄	8.00 ± 0.84	> 32	> 32	> 32
9	8i	3-CH₃OC₆H₄	2.20 ± 0.17	> 32	> 32	> 32
10	8j	Benzofuran-3-yl	12.44 ± 0.96	> 32	> 32	> 32
11	8k	Benzo[b]thiophen-3-yl	>32	> 32	> 32	> 32
12	Ellipticine		̶	0.41 ± 0.02	0.42 ± 0.02	0.42 ± 0.03
13	Donepezil		0.028 ± 0.003	̶	̶	̶

Besides that, all synthesized compounds were also evaluated for their cytotoxic activities against human cancer cell lines, namely human epidermoid carcinoma cancer cell line (KB), human lung cancer cell line (A549) and human hepatoma carcinoma cancer cell line (HepG2) by MTT (3-[4,5-di-methylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay,^71,72 with ellipticine as a reference. The results indicated that all synthesized products have shown no cytotoxic activity against selected cancer cell lines with IC₅₀ > 32 µg/mL (Table 1).

Materials and Methods

Experimental procedures for the synthesis of products 8, in vitro AChE inhibition assay and MTT assay protocol are provided in the supporting information

5-(4-Methoxyphenyl)-2-Methyl-5,7,8,9-Tetrahydro-4H-chromeno[2,3-d]Pyrimidine-4,6(3H)-Dione (8a)

Yield 264 mg (78%), white solid, mp. 268-269 °C. R_f= 0.48 (EtOAc/Acetone 1:20). IR (KBr) 3496, 3265, 3102, 3010, 2943, 2785, 1662, 1602, 1510, 1456, 1366, 1302, 1258, 1243, 1202, 1179, 1150, 1125, 1029, 978, 809, 578 cm⁻¹. ¹H NMR (CDCl₃, 600 MHz): δ 13.19 (1H, s, NH), 7.22 (2H, dd, J = 7.2, 2.4 Hz), 6.74 (2H, dd, J = 7.2, 2.4 Hz), 4.90 (1H, s), 3.72 (3H, s, OCH₃), 2.78-2.73 (2H, m), 2.42-2.32 (2H, m), 2.35 (3H, s, CH₃), 2.09-2.01 (2H, m). ¹³C NMR (CDCl₃, 125 MHz): δ 196.5, 165.0, 164.7, 160.8, 158.4, 158.2, 135.7, 129.4 (2C), 116.1, 113.5 (2C), 103.0, 55.2, 36.9, 32.1, 27.3, 21.2, 20.3. HRMS (ESI+) m/z [M + H]⁺ calc. for: C₁₉H₁₉N₂O₄: 339.1339, found: 339.1340, m/z [M + Na]⁺ calc. for: C₁₉H₁₈N₂NaO₄: 361.1159, found: 361.1154.

3.2. 5-(4-Methylphenyl)-2-Methyl-5,7,8,9-Tetrahydro-4H-chromeno[2,3-d]Pyrimidine-4,6(3H)-Dione (8b)

Yield 258 mg (80%), white solid. R_f= 0.50 (EtOAc/Acetone 1:20). IR (KBr) 3440, 3101, 3038, 2950, 2781, 1656, 1605, 1573, 1479, 1429, 1362, 1304, 1239, 1205, 1179, 1149, 1125, 1064, 1027, 980, 864, 802, 709, 579 cm⁻¹. ¹H NMR (DMSO-d₆, 600 MHz): δ 12.49 (1H, s, NH), 7.09 (2H, d, J = 7.8 Hz), 7.01 (2H, d, J = 7.8 Hz), 4.67 (1H, s), 2.74-2.61 (2H, m), 2.35-2.23 (2H, m), 2.24 (3H, s, CH₃), 2.20 (3H, s, CH₃), 2.00-1.96 (1H, m), 1.91-1.86 (1H, m). ¹³C NMR (DMSO-d₆, 150 MHz): δ 196.2, 165.6, 162.2, 159.9, 158.5, 141.1, 135.5, 128.6 (2C), 127.9 (2C), 115.0, 101.9, 36.5, 31.9, 26.7, 20.9, 20.6, 20.0. HRMS (ESI+) m/z [M + H]⁺ calc. for: C₁₉H₁₉N₂O₃: 323.1390, found: 323.1385, m/z [M + Na]⁺ calc. for: C₁₉H₁₈N₂NaO₃: 345.1210, found: 345.1212.

5-(4-Bromophenyl)-2-Methyl-5,7,8,9-Tetrahydro-4H-chromeno[2,3-d]Pyrimidine-4,6(3H)-Dione (8c)

Yield 314 mg (81%), white solid, mp. 299-301 °C. R_f= 0.51 (EtOAc/Acetone 1:20). IR (KBr) 2920, 2867, 2785, 2650, 1912, 1795, 1679, 1650, 1598, 1501, 1424, 1366, 1327, 1240, 1205, 1186, 1152, 1106, 1065, 1020, 982, 934, 895 cm⁻¹. ¹H NMR (DMSO-d₆, 600 MHz): δ 12.55 (1H, s, NH), 7.41 (2H, dd, J = 7.8, 1.8 Hz), 7.18 (2H, dd, J = 7.8, 1.8 Hz), 4.68 (1H, s), 2.75-2.62 (2H, m), 2.37-2.25 (2H, m), 2.26 (3H, s, CH₃), 2.01-1.96 (1H, m), 1.94-1.87 (1H, m). ¹³C NMR (DMSO-d₆, 150 MHz): δ 196.0, 165.8, 162.0, 159.9, 158.8, 143.2, 130.7 (2C), 130.3 (2C), 119.4, 114.2, 101.1, 36.3, 32.1, 26.6, 20.9, 19.8. HRMS (ESI+) m/z [M + H]⁺ calc. for: C₁₈H₁₆BrN₂O₃: 387.0339 and 389.0319, found: 387.0343 and 389.0326, m/z [M + Na]⁺ calc. for: C₁₈H₁₅BrN₂NaO₃: 409.0159 and 411.0138, found: 409.0162 and 411.0136.

2-Methyl-5-(4-(Trifluoromethyl)Phenyl)-5,7,8,9-Tetrahydro-4H-chromeno[2,3-d]Pyrimidine-4,6(3H)-Dione (8d)

Yield 294 mg (78%), white solid. R_f= 0.49 (EtOAc/Acetone 1:20). IR (KBr) 2920, 2867, 2785, 2650, 1912, 1795, 1679, 1650, 1598, 1501, 1424, 1366, 1327, 1240, 1205, 1186, 1152, 1106, 1065, 1020, 982, 934, 895 cm⁻¹. ¹H NMR (DMSO-d₆, 600 MHz): δ 12.57 (1H, s, NH), 7.59 (2H, d, J = 7.8 Hz), 7.46 (2H, d, J = 7.8 Hz), 4.78 (1H, s), 2.77-2.65 (2H, m), 2.38-2.27 (2H, m), 2.26 (3H, s, CH₃), 2.02-1.98 (1H, m), 1.95-1.89 (1H, m). ¹³C NMR (DMSO-d₆, 150 MHz): δ 196.1, 166.0, 162.0, 160.0, 159.0, 148.4, 128.9, 127.0 (1C, q, J = 31.5 Hz), 124.8 (2C, d, J = 4.5 Hz), 124.2 (1C, q, J = 270 Hz, CF₃), 114.0, 100.8, 36.3, 32.7, 30.6, 26.7, 20.9, 19.8.

5-(4-Chlorophenyl)-2-Methyl-5,7,8,9-Tetrahydro-4H-chromeno[2,3-d]Pyrimidine-4,6(3H)-Dione (8e)

Yield 271 mg (79%), white solid, mp. 293-295 °C. R_f= 0.53 (EtOAc/Acetone 1:20). IR (KBr) 3444, 2935, 2842, 2778, 1668, 1638, 1487, 1405, 1369, 1324, 1249, 1237, 1195, 1176, 1144, 1125, 1083, 1009, 950, 857, 802, 743, 593, 578, 518 cm⁻¹. ¹H NMR (DMSO-d₆, 600 MHz): δ 12.54 (1H, s, NH), 7.27 (2H, dd, J = 6.6, 2.4 Hz), 7.24 (2H, dd, J = 6.6, 1.8 Hz), 4.70 (1H, s), 2.75-2.63 (2H, m), 2.37-2.25 (2H, m), 2.26 (3H, s, CH₃), 2.02-1.96 (1H, m), 1.94-1.87 (1H, m). ¹³C NMR (DMSO-d₆, 150 MHz): δ 196.1, 165.8, 162.1, 160.0, 158.8, 142.9, 131.0, 129.9 (2C), 127.9 (2C), 114.4, 101.2, 36.4, 32.1, 26.7, 20.9, 19.9. HRMS (ESI+) m/z [M + H]⁺ calc. for: C₁₈H₁₆ClN₂O₃: 343.0844, found: 343.0842, m/z [M + Na]⁺ calc. for: C₁₈H₁₅ClN₂NaO₃: 365.0664, found: 365.0651.

5-(3-Bromophenyl)-2-Methyl-5,7,8,9-Tetrahydro-4H-chromeno[2,3-d]Pyrimidine-4,6(3H)-Dione (8f)

Yield 299 mg (77%), white solid, mp. 300-302 °C. R_f= 0.62 (EtOAc/Acetone 1:20). IR (KBr) 3437, 2937, 2837, 2758, 1667, 1638, 1604, 1564, 1493, 1469, 1417, 1370, 1329, 1240, 1196, 1147, 1127, 1069, 972, 825, 785, 696, 672, 608, 586 cm⁻¹. ¹H NMR (DMSO-d₆, 600 MHz): δ 12.57 (1H, s, NH), 7.40 (1H, s), 7.34-7.31 (1H, m), 7.19 (2H, d, J = 4.8 Hz), 4.68 (1H, s), 2.76-2.71 (1H, m), 2.68-2.62 (1H, m), 2.34-2.25 (2H, m), 2.25 (3H, s, CH₃), 2.01-1.96 (1H, m), 1.93-1.87 (1H, m). ¹³C NMR (DMSO-d₆, 125 MHz): δ 196.1, 166.0, 162.0, 160.0, 158.9, 146.5, 130.9, 130.2, 129.3, 127.0, 121.1, 114.1, 100.9, 36.3, 32.4, 26.7, 20.9, 19.8. HRMS (ESI+) m/z [M + H]⁺ calc. for: C₁₈H₁₆BrN₂O₃: 387.0339 and 389.0319, found: 387.0333 and 389.0320, m/z [M + Na]⁺ calc. for: C₁₈H₁₅BrN₂NaO₃: 409.0159 and 411.0138, found: 409.0146 and 411.0127.

2-Methyl-5-(2-Nitrophenyl)-5,7,8,9-Tetrahydro-4H-chromeno[2,3-d]Pyrimidine-4,6(3H)-Dione (8g)

Yield 258 mg (73%), white solid, mp. 273-275 °C. R_f= 0.60 (EtOAc/Acetone 1:20). IR (KBr) 3444, 2937, 2872, 2781, 1674, 1646, 1607, 1532, 1424, 1364, 1327, 1243, 1190, 1154, 1067, 982, 861, 829, 786, 733, 702, 581 cm⁻¹. ¹H NMR (DMSO-d₆, 600 MHz): δ 12.47 (1H, s, NH), 7.81 (1H, d, J = 7.8 Hz), 7.55 (1H, t, J = 7.8 Hz), 7.37 (1H, d, J = 7.8 Hz), 7.36 (1H, t, J = 7.8 Hz), 5.64 (1H, s), 2.70-2.65 (2H, m), 2.34-2.29 (1H, m), 2.25 (3H, s, CH₃), 2.25-2.20 (1H, m), 2.00-1.96 (1H, m), 1.92-1.86 (1H, m). ¹³C NMR (DMSO-d₆, 125 MHz): δ 196.0, 166.1, 161.8, 159.8, 159.1, 149.1, 138.0, 132.9, 130.7, 127.3 123.9, 113.6, 100.6, 36.3, 28.4, 26.7, 20.9, 19.8. HRMS (ESI+) m/z [M + H]⁺ calc. for: C₁₈H₁₆N₃O₅: 354.1085, found: 354.1083, m/z [M + Na]⁺ calc. for: C₁₈H₁₅N₃NaO₅: 376.0904, found: 376.0893.

2-Methyl-5-(3-Nitrophenyl)-5,7,8,9-Tetrahydro-4H-chromeno[2,3-d]Pyrimidine-4,6(3H)-Dione (8h)

Yield 265 mg (73%), white solid, mp. 291-293 °C. R_f= 0.58 (EtOAc/Acetone 1:20). IR (KBr) 3478, 3373, 3094, 3015, 2938, 2877, 2794, 1677, 1663, 1600, 1525, 1429, 1350, 1324, 1241, 1203, 1186, 1154, 1123, 985, 917, 825, 772, 731, 683, 578 cm⁻¹. ¹H NMR (DMSO-d₆, 600 MHz): δ 12.57 (1H, s, NH), 8.07 (1H, t, J = 1.8 Hz), 8.03-8.00 (1H, m), 7.69 (1H, d, J = 7.8 Hz), 7.54 (1H, t, J = 7.8 Hz), 4.83 (1H, s), 2.79-2.73 (1H, m), 2.72-2.66 (1H, m), 2.38-2.32 (1H, m), 2.31-2.26 (1H, m), 2.27 (3H, s, CH₃), 2.04-1.97 (1H, m), 1.96-1.89 (1H, m). ¹³C NMR (DMSO-d₆, 150 MHz): δ 196.1, 166.3, 162.0, 160.0, 159.2, 147.4, 145.9, 134.8, 129.5, 122.7, 121.5, 113.7, 100.5, 36.2, 32.8, 26.7, 20.9, 19.8. HRMS (ESI+) m/z [M + H]⁺ calc. for: C₁₈H₁₆N₃O₅: 354.1085, found: 354.1073, m/z [M + Na]⁺ calc. for: C₁₈H₁₅N₃NaO₅: 376.0904, found: 376.0887.

5-(3-Methoxyphenyl)-2-Methyl-5,7,8,9-Tetrahydro-4H-chromeno[2,3-d]Pyrimidine-4,6(3H)-Dione (8i)

Yield 257 mg (76%), white solid, mp. 282-283 °C. R_f= 0.65 (EtOAc/Acetone 1:20). IR (KBr) 3429, 3000, 2936, 2869, 1770, 1664, 1635, 1596, 1487, 1460, 1363, 1325, 1314, 1243, 1188, 1160, 1036, 980, 823, 780, 693, 617, 572, 457 cm⁻¹. ¹H NMR (DMSO-d₆, 600 MHz): δ 12.52 (1H, s, NH), 7.14 (1H, t, J = 7.8 Hz), 6.77 (1H, d, J = 1.6 Hz), 6.76 (1H, td, J = 7.8 Hz), 6.72 (1H, dd, J = 7.8, 2.4 Hz), 4.71 (1H, s), 3.70 (3H, s), 2.76-2.71 (1H, m), 2.68-2.63 (1H, m), 2.36-2.27 (2H, m), 2.25 (3H, s, CH₃), 2.02-1.97 (1H, m), 1.93-1.89 (1H, m). ¹³C NMR (DMSO-d₆, 150 MHz): δ 196.1, 165.7, 162.1, 160.0, 158.9, 158.5, 145.3, 129.0, 120.0, 114.6, 114.4, 11.2, 101.5, 54.8, 36.4, 32.1, 26.6, 20.9, 19.9. HRMS (ESI+) m/z [M + H]⁺ calc. for: C₁₉H₁₉N₂O₄: 339.1339, found: 339.1333, m/z [M + Na]⁺ calc. for: C₁₉H₁₈N₂NaO₄: 361.1159, found: 361.1152.

5-(Benzofuran-3-yl)-2-Methyl-5,7,8,9-Tetrahydro-4H-chromeno[2,3-d]Pyrimidine-4,6(3H)-Dione (8j)

Yield 233 mg (67%), white solid, mp. 325-326 °C. R_f= 0.42 (EtOAc/Acetone 1:20). IR (KBr) 3428, 2859, 2781, 1673, 1638, 1607, 1449, 1364, 1328, 1239, 1190, 1153, 1127, 1099, 1080, 1028, 979, 950, 854, 802 cm⁻¹. ¹H NMR (DMSO-d₆, 600 MHz): δ 12.58 (1H, s, NH), 7.77 (1H, s), 7.59 (1H, dd, J = 7.2, 0.6 Hz), 7.49 (1H, dd, J = 7.2, 0.6 Hz), 7.25 (1H, td, J = 7.2, 1.2 Hz), 7.21 (1H, td, J = 7.2, 1.2 Hz), 4.98 (1H, s), 2.79-2.73 (1H, m), 2.71-2.65 (1H, m), 2.35-2.25 (2H, m), 2.25 (3H, s, CH₃), 2.02-1.96 (1H, m), 1.92-1.86 (1H, m). ¹³C NMR (DMSO-d₆, 125 MHz): δ 196.1, 166.0, 162.1, 160.3, 158.7, 154.7, 143.6, 126.3, 123.9, 122.5, 122.1, 120.0, 113.2, 111.3, 100.0, 36.3, 26.6, 22.5, 20.9, 19.9.

5-(Benzo[b]Thiophen-3-yl)-2-Methyl-5,7,8,9-Tetrahydro-4H-chromeno[2,3-d]Pyrimidine-4,6(3H)-Dione (8k)

Yield 230 mg (63%), white solid, mp. 323-324 °C. R_f= 0.48 (EtOAc/Acetone 1:20). IR (KBr) 3422, 3050, 3005, 2939, 2866, 2775, 1671, 1634, 1601, 1490, 1457, 1424, 1363, 1325, 1312, 1238, 1189, 1150, 1126, 1055, 1026, 979, 907, 890, 797, 767, 742, 575 cm⁻¹. ¹H NMR (DMSO-d₆, 600 MHz): δ 12.48 (1H, s, NH), 8.14 (1H, d, J = 7.8 Hz), 7.88 (1H, d, J = 7.8 Hz), 7.40 (1H, td, J = 7.8, 1.2 Hz), 7.36 (1H, s), 7.32 (1H, t, J = 7.8 Hz), 5.18 (1H, s), 2.78-2.72 (1H, m), 2.71-2.65 (1H, m), 2.35-2.28 (1H, m), 2.27-2.22 (1H, m), 2.25 (3H, s, CH₃), 2.02-1.95 (1H, m), 1.92-1.84 (1H, m). ¹³C NMR (DMSO-d₆, 150 MHz): δ 196.5, 1656.0, 162.6, 160.5, 158.9, 140.1, 139.9, 138.3, 125.7, 124.4, 124.2, 123.4, 123.0, 115.2, 101.9, 36.9, 27.2, 26.6, 21.4, 20.4. HRMS (ESI+) m/z [M + Na]⁺ calc. for: C₂₀H₁₆N₂NaO₃S: 387.0774, found: 387.0755.

2-Amino-4-(4-Methoxyphenyl)-5-oxo-5,6,7,8-Tetrahydro-4H-Chromene-3-Carbonitrile (6a)

Yield 263 mg (89%), white solid, mp. 224-225 °C. IR (KBr) 3459, 3322, 3211, 3175, 2924, 2186, 1682, 1663, 1601, 1509, 1450, 1409, 1365, 1259, 1243, 1210, 1171, 1132, 1067, 1030, 1001, 895, 843, 779, 696, 626, 566, 535 cm⁻¹. ¹H NMR (CDCl₃, 600 MHz): δ 7.16 (2H, dd, J = 6.6, 2.4 Hz), 6.82 (2H, dd, J = 6.6, 2.4 Hz), 4.52 (2H, s, NH₂), 4.39 (1H, s), 3.77 (3H, s, OCH₃), 2.63-2.51 (2H, m), 2.41-2.30 (2H, m), 2.08-1.95 (2H, m). ¹³C NMR (CDCl₃, 125 MHz): δ 196.0, 162.9, 158.7, 157.4, 135.5, 128.7 (2C), 118.7, 115.5, 114.0 (2C), 63.8, 55.2, 36.8, 34.7, 27.0, 20.1.

Conclusions

In summary, new pyrano[2,3-d]pyrimidine compounds have been synthesized in moderate to good yields using a “one-pot” two-step multicomponent reaction under microwave irradiation. The result of cytotoxic activity against cancer cells (KB, HepG2, and A549 cells) revealed that active products exhibited no cytotoxicity, suggesting a safety profile of these products. With respect to the AChE inhibitory activity, it can be concluded that almost all of the products displayed moderate to good AChE inhibitory activity. Products 8i possessing methoxy group at meta-position on phenyl group was found to be the most active inhibitor against AChE with IC₅₀ values of 2.20 ± 0.17 µg/mL. Besides that, products 8c (Ar = 4-BrC₆H₄), 8d (Ar = 4-CF₃C₆H₄), and 8f (Ar = 3-BrC₆H₄) possessed promising AChE inhibitory activity. Accordingly, pyrano[2,3-d]pyrimidine derivatives deserve further investigations as potential candidates for the treatment of AD.

Supplemental Material

sj-doc-1-npx-10.1177_1934578X231201037 - Supplemental material for Synthesis and Evaluation of Acetylcholinesterase Inhibitory and Cytotoxic Activities of Pyrano[2,3-d]pyrimidines

Supplemental material, sj-doc-1-npx-10.1177_1934578X231201037 for Synthesis and Evaluation of Acetylcholinesterase Inhibitory and Cytotoxic Activities of Pyrano[2,3-d]pyrimidines by Nguyen Ha Thanh, Nguyen Thi Quynh Giang, Nguyen Van Ha, Hoang Thi Phuong, Le Nhat Thuy Giang, Nguyen Tuan Anh, Ba Thi Cham, Le Duc Huy, Dang Thi Tuyet Anh, Phan Van Kiem and Nguyen Van Tuyen in Natural Product Communications

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethical Approval

Our institution does not require ethical approval for reporting individual cases or case series.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Institute of Chemistry, Vietnam Academy of Science and Technology (grant number VHH.2023.01).

Statement of Human and Animal Rights

This article does not contain any studies with human or animal subjects.

Statement of Informed Consent

There are no human subjects in this article and informed consent is not applicable.

Supplemental Material

Supplemental material for this article is available online.

ORCID iDs

Nguyen Ha Thanh

Phan Van Kiem

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Supplementary Material

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Synthesis and Evaluation of Acetylcholinesterase Inhibitory and Cytotoxic Activities of Pyrano[2,3- d ]pyrimidines

Abstract

Keywords

Introduction

Results and Discussion

Materials and Methods

5-(4-Methoxyphenyl)-2-Methyl-5,7,8,9-Tetrahydro-4H-chromeno[2,3-d]Pyrimidine-4,6(3H)-Dione (8a)

5-(4-Bromophenyl)-2-Methyl-5,7,8,9-Tetrahydro-4H-chromeno[2,3-d]Pyrimidine-4,6(3H)-Dione (8c)

2-Methyl-5-(4-(Trifluoromethyl)Phenyl)-5,7,8,9-Tetrahydro-4H-chromeno[2,3-d]Pyrimidine-4,6(3H)-Dione (8d)

5-(4-Chlorophenyl)-2-Methyl-5,7,8,9-Tetrahydro-4H-chromeno[2,3-d]Pyrimidine-4,6(3H)-Dione (8e)

5-(3-Bromophenyl)-2-Methyl-5,7,8,9-Tetrahydro-4H-chromeno[2,3-d]Pyrimidine-4,6(3H)-Dione (8f)

2-Methyl-5-(2-Nitrophenyl)-5,7,8,9-Tetrahydro-4H-chromeno[2,3-d]Pyrimidine-4,6(3H)-Dione (8g)

2-Methyl-5-(3-Nitrophenyl)-5,7,8,9-Tetrahydro-4H-chromeno[2,3-d]Pyrimidine-4,6(3H)-Dione (8h)

5-(3-Methoxyphenyl)-2-Methyl-5,7,8,9-Tetrahydro-4H-chromeno[2,3-d]Pyrimidine-4,6(3H)-Dione (8i)

5-(Benzofuran-3-yl)-2-Methyl-5,7,8,9-Tetrahydro-4H-chromeno[2,3-d]Pyrimidine-4,6(3H)-Dione (8j)

5-(Benzo[b]Thiophen-3-yl)-2-Methyl-5,7,8,9-Tetrahydro-4H-chromeno[2,3-d]Pyrimidine-4,6(3H)-Dione (8k)

2-Amino-4-(4-Methoxyphenyl)-5-oxo-5,6,7,8-Tetrahydro-4H-Chromene-3-Carbonitrile (6a)

Conclusions

Supplemental Material

sj-doc-1-npx-10.1177_1934578X231201037 - Supplemental material for Synthesis and Evaluation of Acetylcholinesterase Inhibitory and Cytotoxic Activities of Pyrano[2,3-d]pyrimidines

Footnotes

Declaration of Conflicting Interests

Ethical Approval

Funding

Statement of Human and Animal Rights

Statement of Informed Consent

Supplemental Material

ORCID iDs

References

Supplementary Material