Novel Spiro-pyrrolizidine-Oxindole and Spiropyrrolidine-Oxindoles: Green synthesis under Classical, Ultrasonic, and microwave conditions and Molecular docking simulation for antitumor and type 2 diabetes

Dina F. Katowah; Huwaida M.E. Hassaneen; Thoraya A. Farghaly

doi:10.1016/j.arabjc.2022.103930

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Original article

07 2022

:15;

103930

doi:

10.1016/j.arabjc.2022.103930

Novel Spiro-pyrrolizidine-Oxindole and Spiropyrrolidine-Oxindoles: Green synthesis under Classical, Ultrasonic, and microwave conditions and Molecular docking simulation for antitumor and type 2 diabetes

Novel Spiro-pyrrolizidine-Oxindole and Spiropyrrolidine-Oxindoles

Dina F. Katowah^{^a}, Huwaida M.E. Hassaneen^{^b}, Thoraya A. Farghaly^{^a,⁎}

a Department of Chemistry, Faculty of Applied Science, Umm Al-Qura University, Makkah, Saudi Arabia

b Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt

⁎Corresponding author. tamohamed@uqu.edu.sa (Thoraya A. Farghaly) thoraya-f@hotmail.com (Thoraya A. Farghaly) thoraya-f@cu.edu.eg (Thoraya A. Farghaly)

Received: 2022-2-25, Accepted: 2022-4-16,

Disclaimer:
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.

Peer review under responsibility of King Saud University.

Abstract

Novel spiropyrrolizine / pyrrolidineoxindole moieties were synthesized chemo-, and regio-selectively in high yields from knoevenagel reaction of bis[arylmethylidene]piperidin-4-ones, isatin and L-proline or sarcosine under classical, ultrasonic, and microwave conditions. Seven derivatives of the synthesized dispiro-pyrrolizidine-oxindole and spiropyrrolidine were screened for their antitumor activity against two cell lines MCF-7 (breast cancer) and HEPG2 (liver cancer). The results of biological activity indicated that the tested derivatives showed potent activity against breast cancer cell MCF-7. Molecular docking simulation screening studies of the synthesized products with each of the receptors of (3hb5) for breast cancer and (4k9g) for liver cancer and their interaction with 1H5U of glycogen phosphorylase B, type 2 diabetes drug were examined. The docking study of dispiro-pyrrolizidine-oxindole and spiropyrrolidine showed promising results with several derivatives.

Keywords

Spiropyrrolizineoxindole

Spiropyrrolidine oxindole

Glycogen metabolism

Antidiabates

Dispiroheterocyclic

1 Introduction

In full swing, scientists are searching day and night for anti-cancer drugs because of the side effects of the drugs circulating in the market, in addition to the body's resistance to these drugs (Richardson et al., 1988). Cancer of all kinds is one of the terrifying diseases whose name is associated with death. The number of deaths from this disease is increasing due to the increase in its causes and the side effects of chemotherapy (Sung et al., 2021). On the other hand, diabetes is a well-established disease that occurs when the insulin produced by the pancreas is not sufficiently produced or when the body cannot effectively use the insulin produced. Type 2 diabetes that is not dependent on insulin, or appears in adults, results from the body's ineffective use of insulin. The majority of diabetic patients have type 2 diabetes (Diabetes, 2021). Glycogen phosphorylase (GP) inhibition has been proposed as a therapeutic strategy for type 2 diabetes treatment (Oikonomakos et al., 2005; Somsák et al., 2008). Inhibition of this enzyme by potent and selective inhibitors, will lead to antihyperglycemic drugs. Glycogen phosphorylase is a typical allosteric protein with five different ligand-binding sites, providing multiple opportunities to modulate enzyme activity. Spiro heterocycles are naturally occurring substances with biological activities (James et al., 1990). Also, hybrid molecules like pyrrolidine, pyrrolizine and oxindole pharmacophores which had a wide spectrum of biological activities like antimicrobial and anticancer (Hassaneen et al, 2017; Hati et al., 2016; Freeman-Cook et al., 2007; Engen et al., 2014; Almansour et al., 2014; Mohareb et al., 2014; Khan et al., 2014; Kumar et al., 2021; Wei et al., 2012; Chen et al., 2009; Dandia et al., 2017; Arumugam et al., 2018; Nesi et al., 2013; Hanna et al., 2012 ). One method from the several methods to generate pyrrolidine ring (Poomathi et al., 2015; Hemamalini et al., 2011; Ghandi et al., 2009; Shahrestani et al., 2019; Altowyan et al., 2022 ) is 1,3-dipolar cycloaddition of azomethineylides which used to synthesize many dispiroheterocyclic systems with the definite dipolarophiles (Hassaneen et al., 2017; Barakat et al., 2021a; Barakat et al., 2021b; Islam et al., 2021a;Islam et al., 2021b; Islam et al., 2022; Al-Majid et al., 2021; Nájera and Sansano, 2019; Rajkumar et al., 2016 ). Scientists are making an extensive effort to improve the yield of synthesized heterocyclic compounds by using nano-catalysts or different methods of heating such as microwave, ultrasound or reflux and compare the percentage yield of these methods to get the best results. Nano-catalysts and a variety of heating techniques, such as microwave, ultrasound, and reflux, are among the many tools scientists are using to increase the yield of synthetic heterocyclic compounds, with the goal of determining which approach produces the highest percentage yield. Ultrasound form hot spots during acoustic cavitations which serve to increase reaction rates and yields without using rough conditions (Rezaei et al., 2012; Jadidi et al., 2008; Alaoui et al., 2018; Dandia et al., 2020 ). Microwave (MW) method has used for synthesis spiropyrrolidine oxindole derivatives, a lot of advantages in using this method than conventional heating (Kefayati et al., 2015; Hoz et al., 2005; Buriol et al., 2010; Engen et al., 2014; Jandourek et al., 2014; Kidwai et al., 1997 ; Dandia et al., 2021a; Dandia et al., 2021b). Where small volumes and solvent-free MW methods are used that have a high level of chemo-, regio-, and stereoselectivity in them Spiro-oxindole derivatives were made under safe conditions using catalysts in aquas medium (Dandia et al., 2021c; Dandia et al., 2011). There were only a few reports on how to make spirooxindole with each of pyrrolidines and pyrrolizidines under ultrasound, Microwave irradiations, and free solvents.

Following on from the foregoing and in continuation of our research into the synthesis of novel biologically active hybrid heterocyclic compounds using green heating methods, (Shaaban et al, 2022; Alnaja et al., 2021; Bumander et al., 2019; Abbas et al., 2014; Farghaly and Riyadh, 2009 ), we are interested in synthesising new series of pyrrolidineoxindole and spiropyrrolizidine moieties under microwave irradiation and ultrasonic conditions in order to increase their yields and decrease their reaction time.

Furthermore, we will test the anticancer efficacy of newly synthesised spiropyrrolizidine / pyrrolidineoxindole derivatives for their antitumor activity. In addition, they will utilise the docking research to examine their interaction with two proteins (3hb5) that are associated with breast cancer and (4k9g) that are associated with liver cancer. Additionally, via docking studies of these derivatives with the 1H5U domain of glycogen phosphorylase B, a type 2 diabetes medication, evaluate the capacity of the produced compounds to suppress the development of type 2 diabetes.

2 Results and discussion

We previously established in our earlier study (Hassaneen et al, 2017) that condensation reaction of isatin (1), amino acids as L-proline (2), or sarcosine (3), and 3,5-bis[phenylmethylidene]-4-oxopiperidine-N-carboxylate (4a-j), was carried out in methanol at 60 °C in 120 min Scheme 1 to produce dispiro-pyrrolizidine-oxindoles (5), or spiropyrrolidine (6) (Hassaneen et al, 2017).

Synthesis of dispiro-pyrrolizidine-oxindoles (5) and spiropyrrolidine(6).

The innovative dispiro-pyrrolizidine-oxindole (9) and spiropyrrolidine (11) series were produced in this work under solvent-free conditions employing ultrasonic and MW irradiation.

Substituted pyrrolizidines (9) were synthesised in high yields using 1,3-dipolar cycloaddition of azomethineylides (8) to the adduct (7) using standard heating and ultrasonic irradiation (comparative results are shown in Scheme 2, Table 1).

A proposed mechanism for the synthesis of compound 9a-e.

Table 1 Synthesis of spiro pyrrolizidine-oxinidole 9a-e.

Ar		Classical		Ultrasonic
Ar		Time (min)	Yield%	Time(min)	Yield%^a
9a	C₆H₅	120	80	30	96
9b	4-MeC₆H₄	120	83	30	88
9c	4-ClC₆H₄	120	82	30	84
9d	2,4-Cl₂C₆H₃	120	85	30	90
9e	2-Thionyl	120	70	30	82

a: isolated yield based on isatin.

One-pot, three component reaction of isatin (1), L-proline (2), and adduct of type (7) in methanol under reflux. As seen in Scheme 1, the reaction began as a condensation reaction between isatin 1 and L-proline 2, which was then decarboxylated to generate an in-situ azomethine ylide intermediate (8). Then, a new form of spiropyrrolizidine-oxinidole (9) was synthesised in high quantities by cycloaddition of 3,5-bis[arylmethylidene]-4-oxipiperidine-N-ethyl (7a-e) with non-stabilized azomethine ylides (8). Highly diastereoselective and regioselective reaction as a single product was produced which confirmed by TLC and GC–mass analysis. Under mild-conditions and low-intensity ultrasound US (cleaning bath) and methanol as a solvent, cycloaddition reactions were carried. It’s note that single product 9 was obtained in each reaction condition. So, it can be suggested that the pathway of this homogeneous reaction suggested from a concerted mechanism in a thermolytic method to a US method (Scheme 1). Increase in the rate of decarboxylation and the formation of ylide (8) might be the reason in increasing the reaction rate, and cause the frequency of collisions between ylide (8) and 3,5-bis[arylmethylidene]-4-oxipiperidine-N-ethyl (7) to increase. Localized hot spots formed during the cavitational collapse due to the energy of these clashes and formation of ylide (8) which provided by short-lived. Next, we decided to change from conventional thermolytic condition for 120 min. to MW heating in a reaction vessel to reduce the reaction time. When heated to 150 °C with a dedicated MW oven, the reaction was completed in 10 min under solvent-free condition, resulting in a 95% yield of synthesized compound (9a) Table 2. Moreover, we confirmed that however method of the conventional thermal-heating affords only moderate yields of the predictable products of the cyclic-condensation reaction, MW irradiation through solvent-free conditions reveals the same products with significantly reduced reaction time and improved yields Table 2. Use of MW equipment for the synthesis allowed conditions Safe and repeatable interaction.

Table 2 % Yield of compound 9a under MW, solvent-free condition.

Time (min)	Temp(^oC)	Yield%^a
10	200	85
8	200	85
5	200	86
10	150	95
5	150	87
10	80	90
10	65	87

a: isolated yield based on isatin.

Similar to this, preparation of spiropyrrolidine-oxindoles (11a-e) in high yields by a three-component reaction of 3,5-bis[arylmethylidene]-4-oxipiperidine-N-ethyl (7a-e) with two equivalents of both of isatin 1 and sarcosine 3 in methanol at reflux and in ultrasonic condition or microwave under solvent-free conditions to obtain the single product (11) Scheme 3, Table 3.

A proposed mechanism for the synthesis of compounds 11a-e.

Table 3 Synthesis of spiropyrrolizidinoxinidole11a-e.

	Ar	Classical		Ultrasonic		Microwave
	Ar	Time (min)	Yield%	Time (min)	Yield%^a	Time (min)	Yield%^a
11a	C₆H₅	120	84	30	95	10	95
11b	4-MeC₆H₄	120	79	30	84	10	90
11c	4-ClC₆H₄	120	80	30	93	10	94
11d	2,4-Cl₂C₆H₃	120	87	30	88	10	93
11e	2-Thionyl	120	87	30	91	10	94

a: isolated yield based on isatin.

The structure of dispiro heterocyclic ring products 11a-e was proved based on the spectral data that extracted from their NMR, IR, Mass spectra as well as their elemental analysis. The IR spectra of all novel spiropyrrolizidines / pyrrolidineoxindole derivatives 9a-e and 11a-e revealed one NH and two C = O at ν = 3421–3251, 1720–1701 and 1716–1678 cm⁻¹, respectively. The ¹H NMR spectrum of compound 11c (Fig. 1) showed the characteristic signals for all protons in the skeleton of this derivative as follows: δ 0.75 triplet signal for CH₃ of ester group, 1.95 singlet signal for N-CH₃ group, 2.94 doublet of doublet for Hb, 3.14 multiplet signal for the two CH₂ groups of pipridinone ring, 3.34 doublet of doublet for Hc, 3.76 quartet signal for CH₂ of ester group, 4.61 doublet of doublet for Ha, 6.56–7.41multiplet with integration of 12 protos for the aromatic protons, 7.54 singlet signal for = CH group and one NH at 10.38 ppm. The regio-chemistry of the products spiropyrrolizidine / pyrrolidineoxindole derivatives 9a-e and 11a-e was confirmed through checking their ¹³C NMR data as for example, ¹³C NMR spectra of derivatives 9a and 11a have the characteristic carbon signals at δ 52.7, 54.2 ppm and 83.4, 88.5 ppm for the two spiro carbons in each derivative (Hassaneen et al, 2017). Also, the two downfield carbon signals at δ172.2, and 204.2 ppm in each derivative 9a and 11a were due to the C = O of oxindole and keto C = O carbons of piperidinone ring system, respectively. The mass spectra of all products spiropyrrolizidine / pyrrolidineoxindole derivatives 9a-e and 11a-e showed expected molecular ion peak for each derivative which confirms the formation of mono-adduct (Fig. 2).

The 1H NMR (DMSO‑d6, 300 MHz) of derivative 11c.

The mass spectrum of compound 11d (Mwt = 615.38).

The usage of methanol in the synthesis of new spiropyrrolizidine / pyrrolidineoxindole derivatives 9a-e and 11a-e by microwave irradiation or ultrasound demonstrated its effectiveness in terms of high yields for each derivative, a straightforward experimental approach, and ease of isolation.

2.1

2.1 Antitumor activity

Selected derivatives of the synthesized spiro compounds 9b,c,e and 11b-e were screened for their antitumor activity against two cell lines MCF-7 and HEPG2 (Table 4). We observed from the obtained data of IC₅₀ in Table 4 that the tested derivatives displayed moderate to excellent cytotoxic activities against the breast cancer MCF-7 cell line with IC₅₀ values ranging from 3.9 to 36.1 μg. 1′'-ethyl-1′-methyl-5′'-(4-methylbenzylidene)-4′-(p-tolyl)dispiro[indoline-3,2′-pyrrolidine-3′,3′'-piperidine]-2,4′'-dione (11b) is the most reactive derivative with IC₅₀ = 3.9 μg in compared with the IC₅₀ = 5.20 μg of the reference cisplatin drug. In addition to two derivatives 9b and 9c showed good activity with IC₅₀ = 7.8 and 9.2 μg. The most potent derivatives as anti-breast cancer derivatives 11b and 9b carrying in their skeletons the methyl (EDG). Within the investigation the result for HEPG2 in Table 4, we noted that the most reactive spiro-derivative is 11b with IC₅₀ = 5.7 μg that is near to the IC₅₀ = 3.67 μg of the reference cisplatin drug. The other two spiro-derivatives 9c and 9b have good activity with IC₅₀ = 9.7 and 10.6 μg. The other tested spiro-pyrazoles showed moderate activity with IC₅₀ ranging from 24.8 to 46.2 μg.

Table 4 The results of IC₅₀ (µg) of the antitumor activity of derivatives 9b,c,e and 11b-e against two cell lines MCF-7 and HEPG2.

Compd. No.	MCF-7	HEPG2
9b	7.8	10.6
9c	9.2	9.7
9e	21.0	28.7
11b	3.9	5.7
11c	35.9	37.2
11d	18.8	24.8
11e	36.1	46.2
Cisplatin	5.20	3.67

2.2

2.2 Docking study

2.2.1

2.2.1 Docking study with the receptors of (3hb5) for breast cancer and (4k9g) for liver cancer

To understand the obtained antitumor results depending on a structural bases, all synthesized spiro-derivatives 9a-e and 11a-e were evaluated through docking techniques (Table 5 and 6) with the receptors of (3hb5) for breast cancer and (4k9g) for liver cancer. Docking simulation was performed in this study using Molecular Operating Environment MOE-Dock 2014 software (MOE, 2014). All the interaction energies and different calculations were calculated. From the docking results of the spiro-synthesized derivatives 9a-e and 11a-e with the receptors of (3hb5) for breast cancer, they indicated that all derivatives were interacted with the active cites of (3hb5) with binding energies −6.5630 to −2.1721 Kcal/mol (Figs. 3 and 4) except derivative 9d. The most reactive derivative in the series of spiro-compounds 9a-e was found to be 9b with docking score − 5.7909 Kcal/mol with only H- acceptor from ARG 37 to the C = O of piperidone ring. In case of series 11a-e, spiro-derivative 11b is the most reactive compound with binding score = -6.5630 Kcal/mol which formed three types of interactions namely, H-acceptor, pi-cation and pi-pi with the amino acids GLY 92, ARG 37 and PHE 192, respectively. On the other hand, docking the spiro-compounds 9a-e didn’t show any interaction with the active sites of receptor 4k9g (Table 6 & Fig. 5). But, all derivatives 11a-e involved in the interaction with 4k9g with energy score = -5.5473 to −4.8955 Kcal/mol through H-acceptor, pi-cation and pi-H. The essential parts of the spiro-compounds 11a-d that involved in the interaction to the active site of the protein receptor 4k9g are C = O of indole, nitrogen atom of piperidone, the aryl ring of arylidene moieties.

Table 5 Docking results of the new synthesized derivatives 9a-e and 11a-e with the receptors of (3hb5) for breast cancer.

Compd.	Ligand moiety	Receptor site	Interacting residues (Type of interaction)	Distance (^oA)	E (kcal/mol)	Docking score (kcal/mol)
9a	6-ring	CG LEU 93 (X)	pi-H	4.07	−0.6	− 5.0609
9b	O 38	NH₂ ARG 37 (X)	H-acceptor	3.12	−1.3	− 5.7909
9c	CL 64 N 5 6-ring 6-ring	O LEU 64 (X) NH2 ARG 37 (X) NE ARG 37 (X) NZ LYS 195 (X)	H-donor H-acceptor pi-cation pi-cation	3.23 2.99 4.02 4.23	−0.5 −3.8 −1.0 −0.8	−5.2109
9d	---	---	---	---	---	---
9e	N 13 O 41 6-ring	NH2 ARG 37 (X) N GLY 92 (X) NE ARG 37 (X)	H-acceptor H-acceptor pi-cation	3.15 3.17 3.92	−2.1 −1.3 −1.4	−2.1721
11a	6-ring	6-ring PHE 192 (X)	pi-pi	3.98	−0.0	−5.7153
11b	O 39 6-ring 6-ring	N GLY 92 (X) NE ARG 37 (X) 6-ring PHE 192 (X)	H-acceptor pi-cation pi-pi	2.83 3.85 3.75	−4.2 −1.5 −0.0	−6.5630
11c	CL 60 O 39	OD1 ASN 90 (X) NH2 ARG 37 (X)	H-donor H-acceptor	3.42 2.55	−0.7 −2.4	−5.3711
11d	CL 57 O 40	O ALA 106 (X) NZ LYS 195 (X)	H-donor H-acceptor	3.59 2.79	−1.1 −6.1	−5.1334
11e	N 15 O 39 5-ring	NH2 ARG 37 (X) NH2 ARG 37 (X) CA GLY 13 (X)	H-acceptor H-acceptor pi-H	3.22 2.76 4.09	−1.1 −2.0 −0.6	−6.1817

Table 6 Docking results of the new synthesized derivatives 9a-e and 11a-e with the receptors of (4k9g) for liver cancer.

Compd.	Ligand moiety	Receptor site	Interacting residues (Type of interaction)	Distance (^oA)	E (kcal/mol)	Docking score (kcal/mol)
9a	---	---	---	---	---	---
9b	---	---	---	---	---	---
9c	---	---	---	---	---	---
9d	---	---	---	---	---	−5.8396
9e	---	---	---	---	---	---
11a	6-ring	N PRO 1 (A)	pi-cation	3.63	−1.4	−4.8955
11b	O 39	NE1 TRP 108 (A)	H-acceptor	2.84	−2.1	−5.5473
11c	6-ring 6-ring	CA TYR 36 (A) 6-ring TRP 108 (A)	pi-H pi-pi	4.68 3.88	−0.6 −0.0	−5.2285
11d	N 5 O 39	NE2 GLN 35 (A) NE2 GLN 35 (A)	H-acceptor H-acceptor	3.44 3.02	−1.1 −1.4	−5.4566
11e	5-ring	CA TYR 36 (A)	pi-H	4.02	−0.6	−4.9266

2D and contact performance of docked compounds 9b and 11a into the active site of 3hb5.

2D and contact performance of docked compounds 11b and 11e into the active site of 3hb5.

2D and surface interaction of docked compounds 11b and 11d into the active site of 4k9g.

2.2.2

2.2.2 Docking study with glycogen phosphorylase B (PDB code: 1H5U)

Pyrrolidine and oxindole containing compounds are parts of antidiabetic α-glucosidase inhibitors (Trapero and Llebaria, 2012; Hamed, 2018; Zhu et al., 2021 ). This finding encourages us to test the interaction of all synthesized dispiro-pyrrolizidine-oxindoles (9a-e) and spiropyrrolidinebisoxindoles (11a-e) with glycogen phosphorylase B to inhibit the type 2 diabetes. The X- ray crystallography structure was reported for (PDB code: 1H5U). The behaviour of the synthesised products in binding site of the target protein was shown in Fig. 6 which predict the binding modes, affinities, and orientations of compounds (9a-e, 11a-e) at the active sites of the protein, docking scores were listed in Table 7. Dispiro-pyrrolizidine-oxindoles (9) showed more activity than spiropyrrolidinebisoxindoles (11). The carbonyl group of isatin has high activity as it bound with amino acids. In which 9a bounded with Arg 569 (bond length: 2.7 Å), in 9b Arg 589 (bond length: 2.4 Å), In 9d Lys 576 (bond length: 2.4 Å) and Arg 589 (bond length: 1.6 Å), and in 11b. Lys 680(bond length: 2.1 Å) and Thr 676 (bond length: 3.0 Å).The Nitrogen atom of N-ethylpiperidin-4-one also showed activity towards amino acids Lys 576 as in 9a (bond length: 2.3 Å), in 9b (bond length: 2.1 Å), in 9d (bond length: 2.78 Å), and Asn 284 (bond length: 2.5 Å), and in 11b (bond length: 2.4 Å). The carbonyl group of same rings piperidin-4-one showed high activity in binding with amino acids of (PDB code: 1H5U), in 9a Thr 676 (bond length: 2.8 Å), Gly 677 (bond length: 2.8 Å), in 9b Thr 676 (bond length: 2.7 Å), Gly 677 (bond length: 2.6 Å), and in 11b Thr 676 (bond length: 2.4 Å). The data showed that 9a, 9b, 9d, 11b have promising activity.

2D, 3D of the promising compounds against glycogen phosphorylase B (PDB code: 1H5U).

Table 7 Molecular docking simulation of compounds 9a-e, 11a-e with glycogen phosphorylase B (PDB code: 1H5U).

Compound	S (score)
9a	−10.61
9b	−12.37
9c	−12.41
9d	−12.40
11a	−8.79
11b	−6.14
11c	−9.96
11d	−12.00

3 Conclusion

Novel of spiropyrrolizidine / pyrrolidineoxindole moieties were synthesized under classical, ultrasonic, and microwave conditions in high yields. US method applied in methanol at 30 min and lower reaction temperature with high yield. In MW the reaction was completed in 10 min under solvent-free condition, resulting in high yield of synthesized compounds. Seven derivatives of the synthesized dispiro-pyrrolizidine-oxindoles and spiropyrrolidine were screened for their antitumor activity against two cell lines MCF-7 (breast cancer) and HEPG2 (liver cancer). The results of biological activity indicated that the tested derivatives have potent activity against breast cancer cell MF-6. Molecular docking simulation screening studies of the synthesized products with each of the receptors of (3hb5) for breast cancer and (4k9g) for liver cancer and their interaction with 1H5U of glycogen phosphorylase B, type 2 diabetes drug were examined. The docking study of dispiro-pyrrolizidine-oxindoles and spiropyrrolidine showed promising results with several derivatives.

4 Experimental section

4.1

4.1 Instrumentation

All instruments with their description were cited in supplementary file.

4.2

4.2 Classical heating

Under normal reflux, a mixture of 10 mmol of each of isatin, L-proline or sarcosine, and 5 mmol of 3,5-bis[arylmethylidene]-4-oxipiperidine-N-ethyl in 30 mL of methanol was heated (Table 1-3 ). When the reaction was completed by checking the progress of the reaction using TLC, the solid of 9a-e or 11a-e was collected and purified by recrystallization in ethanol. The physical and spectral data for 9a-e and 11a-e are listed below and their yields are tabulated in Table 1-3 .

4.3

4.3 Ultrasound irradiation

Irradiation at 25–30 °C of a mixture of 1 mmol of each isatin, amino acids as L-proline, or sarcosine and 0.5 mmol of 3,5-bis[arylmethylidene]-4-oxipiperidine-N-ethyl in 10 mL for 30 min using ultrasound irradiation in a water-bath of an ultrasonic cleaner (to avert from the rising of the vapor pressure of methanol and to realize effective cavitation’s in this solvent, bath 50 kHz). The formed solid of 9a-e or 11a-e was filtered and recrystallized from ethanol. The physical and spectral data for 9a-e and 11a-e are listed below and their yields are tabulated in Table 1-3 .

4.4

4.4 MW Irradiation

A 10 mL microwave vessel equipped with a standard cap (vessel commercially furnished by CEM Discover) was filled with isatin (2 equiv), the appropriate L-proline (2 equiv), or sarcosine (2 equiv) and 3,5-bis[arylmethylidene]-4-oxipiperidine-N-ethyl (1equiv) solvent-free at ambient temperature for 10 min, and the products 9a-e and 11a-e were separated in a pure form without further purification. The physical and spectral data for 9a-e and 11a-e are listed below and their yields are tabulated in Table 1-3 .

4.4.1

4.4.1 5′'-benzylidene-1′'-ethyl-1′-phenyl-5′,6′,7′,7a'-tetrahydro-1′H-dispiro[indoline-3,3′-pyrrolizidine-2′,3′'-piperidine]-2,4′'-dione (9a)

M.p. 234–236 °C (Yellow crystals) IR (KBr) cm⁻¹: 3400 (NH), 1720, 1712 (2CO);¹H NMR (DMSO‑d₆) δ 0.86 (CH₂CH₃, t, 3H, J = 7.2 Hz), 2.08 (2CH_2, m, 4H), 2.13–2.16 (CH_2, m, 2H), 2.14–2.20 (1Hb, m, 1H), 2.50 (1Ha, d, J = 10.2 Hz), 2.55–3.20 (m, 4H, 2CH₂), 4.93 (CH₂CH₃, q, 2H, J = 7.2 Hz), 6.68 (Ar-H, d, J = 7.5 Hz, 2H), 6.94 (Ar-H, d, J = 7.5 Hz, 2H), 7.13–7.49 (Ar-H, m, 10H), 7.58 (=CH, s, 1H), 10.34 (NH, brs, 1H) ppm; ¹³C NMR (DMSO‑d₆): δ 13.4 (CH₃), 22.5, 26.4, 31.8, 52.7, 56.9, 60.1, 62.1, 68.2, 83.4, 114.5, 122.2, 126.1, 126.2, 127.9, 128.0, 128.6, 134.0, 134.9, 136.1, 137.5, 139.5, 152.5, 172.2 (C = O), 204.2 (C = O) ppm; MS, m/z (%): 503.26 (100.0%). Anal. calcd.(Found) for C₃₃H₃₃N₃O₂ (503.63): C, 78.70(78.83); H, 6.60(6.58); N, 8.34(8.23).

4.4.2

4.4.2 1′'-ethyl-5′'-(4-methylbenzylidene)-1′-(p-tolyl)-5′,6′,7′,7a'-tetrahydro-1′H-dispiro-[indoline-3,3′-pyrrolizidine-2′,3′'-piperidine]-2,4′'-dione (9b)

M.p. 249–251 °C (Yellow crystals) IR (KBr) cm⁻¹: 3421 (NH), 1715, 1710 (2CO);¹H NMR (DMSO‑d₆) δ 0.86 (CH₂CH₃, t, 3H, J = 7.2 Hz), 1.08 (2CH_2, m, 4H), 2.08 (2CH, m, 2H), 2.13 (1Hb, m, 1H), 2.31 (CH₃, s, 3H), 2.42 (CH₃, s, 3H), 2.55 (1Ha, d, J = 10.2 Hz), 2.57 (m, 4H, 2CH₂), 4.93 (CH₂CH₃, q, 2H, J = 7.2 Hz), 6.57 (Ar-H, d, J = 7.5 Hz, 2H), 6.78 (Ar-H, d, J = 7.5 Hz, 2H), 7.09 (Ar-H, d, J = 7 Hz, 2H), 7.16 (Ar-H, d, J = 7.5 Hz, 2H), 7.21–7.48 (Ar-H, m, 4H), 7.58 (=CH, s, 1H), 10.34 (NH, s, 1H) ppm; MS, m/z (%): 531.29 (100.0%). Anal. calcd.(Found) for C₃₅H₃₇N₃O₂ (531.69): C, 79.06(79.13); H, 7.01(6.94); N, 7.90(7.87).

4.4.3

4.4.3 5′'-(4-chlorobenzylidene)-1′-(4-chlorophenyl)-1′'-ethyl-5′,6′,7′,7a'-tetrahydro-1′H-dispiro[indoline-3,3′-pyrrolizidine-2′,3′'-piperidine]-2,4′'-dione. (9c)

M.p. 230–233 °C (Yellow crystals) IR (KBr) cm⁻¹: 3251 (NH), 1720, 1710 (2CO); ¹H NMR (DMSO‑d₆) δ 0.74 (CH₂CH₃, t, 3H, J = 7.2 Hz), 1.91 (2CH_2, m, 4H), 2.00 (2 CH, m, 2H), 2.20 (1Hb, m, 1H), 3.29 (2CH_2, m, 4H), 3.34 (CH₂CH₃, q, 2H, J = 7.2 Hz), 4.42 (1Ha, d, J = 10.2 Hz), 6.83–7.33 (Ar-H, m, 12H), 7.36 (=CH, s, 1H), 10.43 (NH, s, 1H) ppm; MS, m/z: 571.18 (100.0%). Anal. calcd.(Found) for C₃₃H₃₁Cl₂N₃O₂ (572.52): C, 69.23(69.16); H, 5.46(5.43); N, 7.34(7.57).

4.4.4

4.4.4 5′'-(2,4-dichlorobenzylidene)-1′-(2,4-dichlorophenyl)-1′'-ethyl-5′,6′,7′,7a'-tetrahydro-1′H-dispiro[indoline-3,3′-pyrrolizidine-2′,3′'-piperidine]-2,4′'-dione. (9d)

M.p. over 300 °C (Yellow crystals) IR (KBr) cm⁻¹: 3255 (NH), 1710, 1681 (2CO); ¹H NMR (DMSO‑d₆) δ 0.67 (CH₂CH₃, t, 3H, J = 7.2 Hz), 1.92 (2 CH_2, m, 4H), 2.00 (2 CH, m, 2H), 2.20 (1Hb, m, 1H), 3.34 (2CH_2, m, 4H), 3.77 (CH₂CH₃, q, 2H, J = 7.2 Hz), 4.82 (1Ha, d, J = 10.2 Hz), 6.64 (Ar-H, d, J = 7.5 Hz, 1H), 6.83 (Ar-H, d, J = 7.5 Hz, 1H), 7.07–7.67 (ArH, m, 8H), 7.95 (=CH, s, 1H), 10.59 (NH, s, 1H) ppm;; MS, m/z (%): 639.10 (78.2%). Anal. calcd. (Found) for C₃₃H₂₉Cl₄N₃O₂ (641.41): C, 61.79(61.69); H, 4.56(4.41); N, 6.55(6.49).

4.4.5

4.4.5 1′'-Ethyl-5′'-(2-thienyl)-1′-(2-thienyl)-5′,6′,7′,7a'-tetrahydro-1′H-dispiro[indoline-3,3′-pyrrolizidine-2′,3′'-piperidine]-2,4′'-dione (9e)

M.p over 300 °C (Yellow crystals) IR (KBr) cm⁻¹: 3253 (NH), 1701, 1678 (2CO); ¹H NMR (DMSO‑d₆) δ 1.11 (CH₂CH₃, t, 3H, J = 7.2 Hz), 1.64 (2 CH_2, m, 4H), 2.18 (2 CH, m, 2H), 2.20 (1Hb, m, 1H), 2.40 (2CH_2, m, 4H), 3.78 (CH₂CH₃, q, 2H, J = 7.2 Hz), 4.50 (1Ha, d, J = 10.2 Hz), 6.81–7.93 (Ar-H and thiophene-H, m, 10H), 7.81 (=CH, s, 1H), 10.45 (NH, s, 1H,) ppm; MS, m/z: 517 (M⁺+2, 27%), 515 (M⁺, 49%). Anal. calcd. (Found) for C₂₉H₂₉N₃O₂S₂ (515.69): C, 67.54(67.32); H, 5.67(5.45); N, 8.15(8.03).

4.4.6

4.4.6 5′'-Benzylidene-1′'-ethyl-1′-methyl-4′-phenyldispiro[indoline-3,2′-pyrrolidine-3′,3′'-piperidine]-2,4′'-dione. (11a)

M.p. 232–234 °C (Colourless crystals) IR (KBr) cm⁻¹: 3253 (NH), 1720, 1713 (2CO); ¹H NMR (DMSO‑d₆): δ 0.74 (CH₂CH₃, t, 3H, J = 7 Hz), 1.96 (CH₃, s, 3H), 2.82 (Hb, dd, 1H, J = 9.0, 7.0 Hz), 3.15 (2CH₂, m, 4H), 3.30 (1Hc, dd, 1H, J = 10.7, 7.0 Hz), 3.78 (CH₂CH₃, q, 2H, J = 7.2 Hz), 4.60 (1Ha, dd, 1H, J = 10.7, 9.0 Hz), 6.55–7.17 (Ar-H, m, 14H), 7.20 (=CH, s, 1H), 10.27 (NH, s, 1H) ppm; ¹³C NMR (DMSO‑d₆) δ 13.7, 29.8, 40.1, 53.3, 54.2, 56.9, 57.2, 64.2, 88.5, 114.5, 122.2, 125.7, 126.3, 126.4, 127.4, 127.8, 128.2, 128.6, 134.2, 135.4, 137.0, 139.5, 140.2, 152.9, 172.2, 204.2 ppm; MS, m/z (%):477.24 (100.0%). Anal. calcd.(Found) for C₃₁H₃₁N₃O₂ (477.60): C, 77.96(77.87); H, 6.54(6.42); N, 8.80(8.74).

4.4.7

4.4.7 1′'-Ethyl-1′-methyl-5′'-(4-methylbenzylidene)-4′-(p-tolyl)dispiro[indoline-3,2′-pyrrolidine-3′,3′'-piperidine]-2,4′'-dione.(11b)

M.p. 242–245 °C (Yellow crystals) IR (KBr) cm⁻¹: 3251 (NH), 1720, 1712 (2CO); ¹H NMR (DMSO‑d₆): δ 0.76 (CH₂CH₃, t, 3H, J = 7 Hz), 1.95 (CH₃, s, 3H), 2.70 (CH₃, s, 3H), 2.92 (Hb, dd, 1H, J = 9.0, 7.0 Hz), 3.14 (2CH₂, m, 4H), 3.17 (CH₃, s, 3H), 3.28 (CH₂CH₃, q, 2H, J = 7.2 Hz), 3.89 (1Hc, dd, 1H, J = 10.7, 7.0 Hz), 4.62 (1Ha, dd, 1H, J = 10.7, 9.0 Hz), 6.57–7.16 (Ar-H, m, 12H), 7.19 (=CH, s, 1H), 10.27 (NH, s, 1H) ppm; MS, m/z (%):505 (7.3%), 506 (1.5%). Anal. calcd. (Found) for C₃₃H₃₅N₃O₂ (505.65): C, 78.38(78.29); H, 6.98(6.82); N, 8.31(8.20).

4.4.8

4.4.8 5′'-(4-chlorobenzylidene)-4′-(4-chlorophenyl)-1′'-ethyl-1′-methyldispiro[indoline-3,2′-pyrrolidine-3′,3′'-piperidine]-2,4′'-dione. (11c)

M.p. 253–255 °C (Yellow crystals) IR (KBr) cm⁻¹: 3251 (NH), 1718, 1710 (2CO); ¹H NMR (DMSO‑d₆) δ 0.75 (CH₂CH₃, t, 3H, J = 7.2 Hz), 1.95 (CH₃, s, 3H), 2.94 (Hb, dd, 1H, J = 9.0, 7.0 Hz), 3.14 (2CH₂, m, 4H), 3.34 (1Hc, dd, 1H, J = 10.7, 7.0 Hz), 3. (CH₂CH₃, q, 2H, J = 7.2 Hz), 4.61 (1Ha, dd, 1H, J = 10.7, 9.0 Hz), 6.57 (Ar-H, d, J = 8 Hz, 2H), 6.84 (Ar-H, d, J = 8 Hz, 2H), 7.02–7.41 (Ar-H, m, 8H), 7.54 (=CH, s, 1H), 10.38 (NH, s, 1H) ppm; MS, m/z (%): 546.17 (33.5%). Anal. Calcd. (Found) for C₃₁H₂₉Cl₂N₃O₂ (546.49): C, 68.13 (68.01); H, 5.35 (5.29); N, 7.69 (7.86).

4.4.9

4.4.9 5′'-(2,4-dichlorobenzylidene)-4′-(2,4-dichlorophenyl)-1′'-ethyl-1′-methyldispiro-[indoline-3,2′-pyrrolidine-3′,3′'-piperidine]-2,4′'-dione. (11d)

M.p. over 300 °C (Yellow crystals) IR (KBr) cm⁻¹: 3340 (NH), 1716, 1710 (2CO); ¹H NMR (DMSO‑d₆): δ 0.69 (CH₂CH₃, t, 3H, J = 7.2 Hz), 1.93 (CH₃, s, 3H), 2.51 (Hb, dd, 1H, J = 9.0, 7.0 Hz), 2.88 (2CH₂, m, 4H), 2.94 (1Hc, dd, 1H, J = 10.7, 7.0 Hz), 3.77 (CH₂CH₃, q, 2H, J = 7.2 Hz), 4.96 (1Ha, dd, 1H, J = 10.7, 9.0 Hz), 6.65 (Ar-H, d, J = 7 Hz, 1H), 6.82 (Ar-H, d, J = 7 Hz, 1H), 7.07–7.87 (Ar-H, m, 8H), 7.99 (=CH, s, 1H), 10.55 (NH, s, 1H) ppm; MS, m/z (%):615.09 (4.3%). Anal. calcd. (Found) for C₃₁H₂₇Cl₄N₃O₂ (615.38): C, 60.50 (60.78); H, 4.42 (4.31); N, 6.83 (6.70).

4.4.10

4.4.10 1′'-Ethyl-1′-methyl-5′'-(2-thienyl)-4′-(2-thienyl)-dispiro[indoline-3,2′-pyrrolidine-3′,3′'-piperidine]-2,4′'-dione (11e)

M.p. over 300 °C (Yellow crystals) IR (KBr) cm⁻¹: 3400 (NH), 1720, 1716 (2CO); ¹H NMR (DMSO‑d₆): δ 0.86 (CH₂CH₃, t, 3H, J = 7.2 Hz), 1.94 (CH₃, s, 3H), 2.72 (Hb, dd, 1H, J = 9.0, 7.0 Hz), 2.72 (2CH₂, m, 4H), 3.26 (CH₂CH₃, q, 2H, J = 7.2 Hz), 3.68 (1Hc, dd, 1H, J = 10.7, 7.0 Hz), 4.82 (1Ha, dd, 1H, J = 10.7, 9.0 Hz), 6.61 (Ar-H, d, J = 7.5 Hz, 1H), 6.71–7.38 (Ar-H and thiophene-H, m, 7H), 7.46 (thiophene-H, d, J = 4.8 Hz, 1H), 7.62 (=CH, s, 1H), 7.83 (thiophene-H, d, J = 4.8 Hz, 1H), 10.40 (NH, s, 1H) ppm; MS, m/z (%):649 (64%). Anal. calcd. (Found) for C₂₇H₂₇N₃O₂S₂ (489.65): C, 66.23 (66.07); H, 5.56 (5.38); N, 8.58 (8.61).

4.5

4.5 Antitumor assay

The method for antitumor assay were reported in the literature report (Mosmann, 1983).

4.6

4.6 Molecular docking studies

Molecular docking study was carried out for spiropyrrolizidines / pyrrolidineoxindoles 9a-e and 11a-e using MOE-Dock 2014 software (Inc, 2016). Chemical structures of spiropyrrolizidines / pyrrolidineoxindoles 9a-e and 11a-e were drawn by the MOE-builder and the program force field MMFF94x minimized them. After download the protiens 3hb5, 4k9g and 1H5U for breast cancer, liver cancer and type2 diabetes, respectively, all hydrogen atoms were aded followed by removal the water molecules. After that, docking of spiropyrrolizidines / pyrrolidineoxindoles 9a-e and 11a-e were done.

Acknowledgements

The authors would like to thank the Deanship of Scientific Research at Umm Al-Qura University for supporting this work by Grant Code: (22UQU4350477DSR04)

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Appendix A

Supplementary material

Supplementary data to this article can be found online at https://doi.org/10.1016/j.arabjc.2022.103930.

Appendix A

Supplementary material

The following are the Supplementary data to this article:

Supplementary Data 1

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Introduction

Results and discussion

Antitumor activity
Docking study

Conclusion

Experimental section

Instrumentation
Classical heating
Ultrasound irradiation
MW Irradiation
Antitumor assay
Molecular docking studies

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Novel Spiro-pyrrolizidine-Oxindole and Spiropyrrolidine-Oxindoles: Green synthesis under Classical, Ultrasonic, and microwave conditions and Molecular docking simulation for antitumor and type 2 diabetes

Abstract

Keywords

Spiropyrrolizineoxindole

Spiropyrrolidine oxindole

Glycogen metabolism

Antidiabates

Dispiroheterocyclic

1 Introduction

2 Results and discussion

2.1 Antitumor activity

2.2 Docking study

2.2.1 Docking study with the receptors of (3hb5) for breast cancer and (4k9g) for liver cancer

2.2.2 Docking study with glycogen phosphorylase B (PDB code: 1H5U)

3 Conclusion

4 Experimental section

4.1 Instrumentation

4.2 Classical heating

4.3 Ultrasound irradiation

4.4 MW Irradiation

4.4.1 5′'-benzylidene-1′'-ethyl-1′-phenyl-5′,6′,7′,7a'-tetrahydro-1′H-dispiro[indoline-3,3′-pyrrolizidine-2′,3′'-piperidine]-2,4′'-dione (9a)

4.4.2 1′'-ethyl-5′'-(4-methylbenzylidene)-1′-(p-tolyl)-5′,6′,7′,7a'-tetrahydro-1′H-dispiro-[indoline-3,3′-pyrrolizidine-2′,3′'-piperidine]-2,4′'-dione (9b)

4.4.3 5′'-(4-chlorobenzylidene)-1′-(4-chlorophenyl)-1′'-ethyl-5′,6′,7′,7a'-tetrahydro-1′H-dispiro[indoline-3,3′-pyrrolizidine-2′,3′'-piperidine]-2,4′'-dione. (9c)

4.4.4 5′'-(2,4-dichlorobenzylidene)-1′-(2,4-dichlorophenyl)-1′'-ethyl-5′,6′,7′,7a'-tetrahydro-1′H-dispiro[indoline-3,3′-pyrrolizidine-2′,3′'-piperidine]-2,4′'-dione. (9d)

4.4.5 1′'-Ethyl-5′'-(2-thienyl)-1′-(2-thienyl)-5′,6′,7′,7a'-tetrahydro-1′H-dispiro[indoline-3,3′-pyrrolizidine-2′,3′'-piperidine]-2,4′'-dione (9e)

4.4.6 5′'-Benzylidene-1′'-ethyl-1′-methyl-4′-phenyldispiro[indoline-3,2′-pyrrolidine-3′,3′'-piperidine]-2,4′'-dione. (11a)

4.4.7 1′'-Ethyl-1′-methyl-5′'-(4-methylbenzylidene)-4′-(p-tolyl)dispiro[indoline-3,2′-pyrrolidine-3′,3′'-piperidine]-2,4′'-dione.(11b)

4.4.8 5′'-(4-chlorobenzylidene)-4′-(4-chlorophenyl)-1′'-ethyl-1′-methyldispiro[indoline-3,2′-pyrrolidine-3′,3′'-piperidine]-2,4′'-dione. (11c)

4.4.9 5′'-(2,4-dichlorobenzylidene)-4′-(2,4-dichlorophenyl)-1′'-ethyl-1′-methyldispiro-[indoline-3,2′-pyrrolidine-3′,3′'-piperidine]-2,4′'-dione. (11d)

4.4.10 1′'-Ethyl-1′-methyl-5′'-(2-thienyl)-4′-(2-thienyl)-dispiro[indoline-3,2′-pyrrolidine-3′,3′'-piperidine]-2,4′'-dione (11e)

4.5 Antitumor assay

4.6 Molecular docking studies

Acknowledgements

References

Appendix A

Supplementary material

Appendix A

Supplementary material

Supplementary Data 1

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