Int J Pharm Pharm Sci, Vol 9, Issue 10, 240-244Original Article


SYNTHESIS, CHARACTERIZATION AND EVALUATION OF 4-HYDROXY-1-PHENYL/METHYL-3-(3-SUBSTITUTED-1-(SUBSTITUTEDIMINO)PROPYL)QUINOLINE-2(1H)-ONE DERIVATIVES AND 4-HYDROXY-1-PHENYL/METHYL-3-(1-(SUBSTITUEDIMINO)ETHYL)QUINOLINE-2(1H)-ONE DERIVATIVES AS POSSIBLE ANTICANCER AGENTS

S. N. MAMLE DESAIa*,RUDRAX N. S. PRIOLKARa, HARSHANK A. NAIK KARMALIa, PRABHAV D. AMBEa,
B. S. BIRADARb

aDepartmentof Pharmaceutical Chemistry, P. E. S.’s Rajaram and Tarabai Bandekar College of Pharmacy, Farmagudi, Ponda-Goa. 403401, bDepartmentof Pharmacolgy, P. E. S.’s Rajaram and Tarabai Bandekar College of Pharmacy, Farmagudi, Ponda-Goa. 403401
Email: [email protected]

Received: 23 May 2017 Revised and Accepted: 31 Aug 2017


ABSTRACT

Objective: Synthesis, characterization and evaluation of quinolin-2-one derivatives as possible anticancer agents.

Methods:A series of novel 4-hydroxy-1-phenyl/methyl-3-(3-substituted-1-(substitutedimino)propyl)quinolin-2(1H)-one derivatives IIa(1-5)/IIb(1-5) and 4-hydroxy-1-phenyl/methyl-3-(1-(substituedimino)ethyl)quinolin-2(1H)-one derivatives IIIa(1-3)/IIIb(1-3) were synthesised by nucleophilic addition of substituted anilines on 3-acetyl-4-hydroxy-1-phenyl/methylquinolin-2(1H)-one(a/b) and 4-hydroxy-3-(3-substitutedpropanoyl)-1-phenyl/methyl quinolin-2(1H)-one (Ia/Ib); respectively. The synthesised derivatives were characterised by spectral analysis and were tested for their in vitro anticancer activity against K562 and Hep 3b cell lines by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay method.

Results: The compounds were tested for their in vitro anticancer activity against K562 and Hep 3b cell lines at 10, 20, 25, 30 and 50µg/ml concentration using MTT assay method. The compound 4-hydroxy-3-(3-morpholino-1-(phenylimino)propyl)-1-phenylquinolin-2(1H)-one (IIa-1) showed anticancer activity with IC50 value 20µg as compared to the control against K562 cell lines. The compound 4-hydroxy-1-phenyl-3-(1-(phenylimino)ethyl)quinolin-2(1H)-one (IIIa-1) showed anticancer activity with IC50 value less than 10µg.

Conclusion: The proposed method for the synthesis of novel derivatives is convenient and gives agood yield. Some of the synthesised compounds showed promising anticancer activity against K562 and Hep 3b cell lines. Compound IIa-1 (R=-C6H5; R1=morpholine; R2=C6H5-NH-) exhibited most potent activity against K562 cell lines. Compound IIIa-1 (R=-C6H5; R3=C6H5-NH-) has been proved to be the most cytotoxic compound among the other derivatives against Hep 3b cell lines.

Keywords: Linomide, Quinolin-2-one, Anticancer, MTT assay


INTRODUCTION

The alarming rise of cancer cases has put strains on individuals, families and the society in which they live. The number of cancer cases and related deaths worldwide is related to double over the next 20-40 y. As per a report by world health organisation (WHO), it is estimated the number of new cancer cases will rise by about 70% over the next two decades [1]. There is a significant advancement in drug discovery and the modern chemotherapy has helped to lower the mortality rates. However, there is a need to develop novel bioactive molecules which would overcome the side effects and toxicity caused by the existing antineoplastic agents; without compromising for any therapeutic efficacy.

The quinolin-2-one moiety exhibits a versatile range of biological activity. The natural compounds containing the quinolin-2-one nucleus such as flindersine, dictamnine as well as their synthetic analogues are found to possess pharmacological activity and therapeutic utility [2-5]. Clinical significance of quinolin-2-one is well established and documented in the form of treatment of psychosis, as a β-blocker in anophthalmic preparation, as anantacid and in congestive cardiac failure [6-9].

Literature reviews have indicated linomide (fig.1), a quinolin-2-one derivative as a lead molecule for the development of anticancer agents [10-12]. In continuation of our research works on linomide, we proposed the synthesis of novel linomide analogues by modifying substitutions on ring nitrogen, isosteric replacement of oxygen by substituted nitrogen and preparing mannich bases by exploiting the acidic hydrogen of theacetyl group. The present study aims at evaluating the anticancer activity of the synthesised novel compounds.

Fig.1: Linomide [13]

MATERIALS AND METHODS

Materials

Chemicals used for the synthesis were purchased from Molychem-Mumbai and SD-Fine Chem Ltd; Mumbai. All the reagents and solvents were of laboratory grade. Fourier transform infrared (FTIR) spectra were recorded on Shimadzu IR affinity-1 spectrophotometer by using KBr pellets. The 1H NMR and 13C NMR was recorded on Bruker Avance II 400 NMR spectrometer using deuterated chloroform (CDCl3) or deuterated dimethyl sulfoxide (DMSO-d6) as solvents and tetramethylsilane (TMS) as an internal standard. Chemical shifts are expressed as delta (δ) values in parts per million (ppm). The mass spectra (MS) were recorded on Waters, Q-TOF Micromass.

Scheme 1: Synthesis of compounds IIa(1-5)/IIb(1-5) and IIIa(1-3)/IIIb(1-3)

Synthesis of 4-hydroxy-3-(3-substitutedpropanoyl)-1-phenyl/methyl quinolin-2(1H)-one (Ia/Ib)

A solution of secondary amine (1mmol) and formaldehyde (10mmol) was stirred for five minutes. To this, a solution of compound 3-acetyl-4-hydroxy-1-phenyl/methyl quinolin-2(1H)-one (a/b, synthesized as per literature) (0.01mol) in methanol was added with 0.05ml of 1N HCl and refluxed for 4-5 h[14]. The progress of the reaction was monitored by thin layered chromatography (TLC). The solution was kept overnight for precipitation to take place. The compounds thus obtained were separated by filtration, washed with water and further recrystallized using a suitable solvent.

Synthesis of 4-hydroxy-3-(3-substituted-1-(substituted amino)propyl)-1-phenyl/methyl quinolin-2(1H)-one (II-a/II-b)

Compound I-a/I-b (1mmol) was added to a solution of dimethylformamide (DMF) (0.2mmol) and pyridine (0.2mmol). To this mixture, substituted aniline (0.3mmol) was added and refluxed for 17-24 h. The solution obtained was poured in ice cold water and kept overnight. The solid separated was filtered and recrystallized using a suitable solvent.

Synthesis of 4-hydroxy-1-phenyl/methyl-3-(1-(substituted amino)ethyl)quinolin-2(1H)-one(IIIa/IIIb)

To a solution of thecompound, a/b (3mmol) in DMF, substituted anilines (3.6mmol) were added and the reaction mixture was stirred at 20 °C for 72 h. The completion of the reaction was monitored by TLC. The solution thus obtained was poured in ice cold water and stirred till crystallization took place. The product was filtered and recrystallized using a suitable solvent.

Anticancer activity

The synthesized derivatives were screened for their in vitro anticancer activity against K562 and Hep 3b cell lines by MTT assay method. The cell lines for the anticancer activity were procured from thenational centre for cell science (NCCS), Pune. The cell lines were maintained in 96 wells microtiter plate containing minimum essential medium (MEM) and were supplemented with 10% heat-inactivated foetal calf serum (FCS) containing 5% of a mixture of gentamicin (10 µg), penicillin (100 U/ml) and streptomycin (100 µg/ml); in presence of 5% CO2 at 37 °C for 48-72 h.

The cell lines were treated with 10, 20, 25, 30 and 50 µg/ml solutions of the test compounds in dimethyl sulfoxide (DMSO). After incubation at 37 °C in a humidified atmosphere of 5% CO2, 20 µl of astock solution of MTT (5 mg in 1 ml of sterile phosphate buffered saline) was added to each well and plates were further incubated for 4 h. DMSO was used as a control. The supernatant was carefully aspirated, the precipitated crystals of formazan blue were solubilized by adding DMSO (100 µl) and optical density (OD) was measured at a wavelength of 570 nm by using LISA plus microplate reader. The percentage of surviving cells was calculated using the following formula:

Percentage of surviving cells (%) = x 100

Table 1: List of derivatives IIa/IIb and IIIa/IIIb synthesized in scheme 1

Compound R R1 R2 R3 % yield
IIa-1 -C6H5 Morpholine C6H5-NH- - 90.0
IIa-2 -C6H5 Morpholine 4-Cl-C6H4-NH- - 88.35
IIa-3 -C6H5 N-Methylpiperazine 4-NO2-C6H4-NH- - 86.93
IIa-4 -C6H5 N-Methylpiperazine 4-Cl-C6H4-NH- - 79.36
IIa-5 -C6H5 Piperidine C6H5-NH- - 81.12
IIb-1 -CH3 Morpholine C6H5-NH- - 81.12
IIb-2 -CH3 Morpholine 4-Cl-C6H4-NH- - 93.0
IIb-3 -CH3 N-Methylpiperazine C6H5-NH- - 84.09
IIb-4 -CH3 N-Methylpiperazine 4-Cl-C6H4-NH- - 88.65
IIb-5 -CH3 Piperidine C6H5-NH- - 92.25
IIIa-1 -C6H5 - - C6H5-NH- 82.91
IIIa-2 -C6H5 - - 4-Cl-C6H4-NH- 79.03
IIIa-3 -C6H5 - - 4-Br-C6H4-NH- 84.26
IIIb-1 -CH3 - - C6H5-NH- 85.25
IIIb-2 -CH3 - - 4-Cl-C6H4-NH- 89.12
IIIb-3 -CH3 - - 4-Br-C6H4-NH- 78.03

RESULTS

Spectral data of 4-hydroxy-3-(3-morpholinopropanoyl)-1-phenylquinolin-2(1H)-one(Ia-1)

IR (KBr, cm-1): 3032.10 (aromatic C-H); 2927.94, 2854.65 (aliphatic C-H); 1629.85 (C=O acetyl); 1606.70 (C=O cyclic amide); 1267.23 (C-O-C).

Spectral data of 4-hydroxy-3-(3-(4-methylpiperazin-1-yl)propanoyl)-1-phenylquinolin-2(1H)-one (Ia-2)

IR (KBr, cm-1): 3041.74 (aromatic C-H); 2891.30, 2762.06 (aliphatic C-H);1629.85 (C=O acetyl); 1606.70 (C=O cyclic amide).

Spectral data of 4-hydroxy-1-methyl-3-(3-morpholino-propanoyl) quinolin-2(1H)-one (Ib-1)

IR (KBr, cm-1): 3076.46 (aromatic C-H); 2887.44, 2777.50 (aliphatic C-H); 1631.78 (C=O acetyl); 1606.70 (C=O cyclic amide); 1269.16 (C-O-C).

Spectral data of 4-hydroxy-1-methyl-3-(3-(4-methylpiperazin-1-yl)propanoyl) quinolin-2(1H)-one (Ib-2)

IR (KBr, cm-1): 2912.51, 2762.06 (aliphatic C-H); 1631.78 (-C=O acetyl); 1606.70 (-C=O cyclic amide).

Spectral data of 4-hydroxy-3-(3-morpholino-1-(phenylimino)propyl)-1-phenylquinolin-2(1H)-one (IIa-1)

IR (KBr, cm-1): 3442.94 (O-H stretch); 3099.16 (aromatic C-H); 2922.16 2852.72 (aliphatic C-H); 1643.35 (-C=N); 1610.56 (-C=O cyclic amide); 1271.09 (C-O-C); 1H NMR (CDCl3, δ ppm): 12.50 (s, 1H, OH); 8.27-6.64 (m, 14H, Ar-H); 4.03 (t, 4H, 2,6-CH2 of morpholine); 3.79(t, 2H,-CH2 of 3-propyl); 2.43 (t, 4H, 3,5-CH2 of morpholine); 1.20 (t, 2H,-CH2 of 2-propyl); 13C NMR (CDCl3, δ ppm): 166.17(1C, C=N); 160.63 (1C, C=O amide); 158.28 (1C, C-OH); 132.17-116.02 (19C, aromatic carbon); 75.92 (1C,-CH2 of 3-propyl); 66.02 (2C, 2,6-CH2 of morpholine); 54.85 (2C, 3,5-CH2 of morpholine); 21.03 (1C,-CH2 of 2-propyl); Mass (m/z) = 453 [M+].

Spectral data of 3-(1-((4-chlorophenyl)imino)-3-morpholinopropyl)-4-hydroxy-1-phenylquinolin-2(1H)-one (IIa-2)

IR (KBr, cm-1): 3089.96 (aromatic C-H); 2983.88, 2875.86 (aliphatic C-H); 1645.33 (C=N); 1612.49 (C=O cyclic amide); 744.52 (C-Cl).

Spectral data of 4-hydroxy-1-methyl-3-(3-morpholino-1(-phenylimino)propyl) quinolin-2(1H)-one (IIb-1)

IR (KBr, cm-1): 3012.81 (aromatic C-H);2887.44,2752.42 (aliphatic C-H); 1644.15 (C=N); 1610.56 (-C=O cyclic amide); 1273.02 (C-O-C); 1H NMR (CDCl3, δ ppm): 12.61 (s, 1H, OH); 8.13-6.53 (m, 9H, Ar-H); 4.13 (t, 4H, 2,6-CH2 of morpholine); 3.72 (t, 2H,-CH2 of 3-propyl); 2.61(s, 3H, N-CH3); 2.29 (t, 4H, 3,5-CH2 of morpholine); 1.20 (t, 2H, CH2 of 2-propyl).

Spectral data of 4-hydroxy-1-methyl-3-(3-(4-methylpiperazin-1-yl)-1-(phenylimino)propyl) quinolin-2(1H)-one (IIb-3)

IR (KBr, cm-1): 3039.81 (aromatic C-H); 2891.302779.42 (aliphatic C-H); 1646.27 (C=N); 1612.49 (-C=O cyclic amide); 1H NMR (CDCl3, δ ppm): 12.41 (s, 1H, OH); 8.26-7.21 (m, 9H, Ar-H); 3.72 (s, 3H, N-CH3); 3.21(t, 2H, CH2 of 3-propyl); 2.51 (t, 8H, 2,3,5,6-CH2 of N-Methyl piperazine); 2.01 (s, 3H, N-CH3);1.63 (t, 2H, CH2 of 2-propyl).

Spectral data of compound 3-(1-((4-chlorophenyl)imino)ethyl)-4-hydroxy-1-phenylquinolin-2(1H)-one (IIIa-2)

IR (KBr, cm-1): 3055.24 (aromatic-C-H); 2924.09, 2850.35 (aliphatic C-H); 1656.85 (-C=N); 1612.49 (-C=O cyclic amide); 759.95 (C-Cl); 1H NMR (CDCl3, δ ppm):16.35 (s, 1H, OH); 8.20-6.51 (m, 13H, Ar-H); 2.24 (s, 3H,-CH3); 13C NMR (CDCl3, δ ppm):175.40 (1C, C=N); 167.36 (1C, C=O amide); 161.30 (1C, C-OH); 149.64-110.37 (19C, aromatic carbon); 31.43 (1C, aliphatic carbon); Mass (m/z) = 389 [M+1].

Spectral data of compound 3-(1-((4-bromophenyl)imino)ethyl)-4-hydroxy-1-methylquinolin-2(1H)-one. (IIIa-3)

IR (KBr, cm-1): 3057.17(aromatic-C-H); 2902.87 (aliphatic C-H); 1654.92 (-C=N),1600.92 (-C=O cyclic amide); 704 (C-Br); 1H NMR (CDCl3, δ ppm):16.23(s, 1H, OH), 8.17-6.68(m, 13H, Ar-H); 2.09 (s, 3H,-CH3).

Table 2: Results for anticancer activity on K562 cell line

S.No. Sample Concentration (µg) Absorbance Results as observed IC50 (µg)
1. IIa-1 10 0.350 <50% lysis 20µg
2. 20 0.347 50% lysis
3. 25 0.336 50% lysis
4. 30 0.327 50% lysis
5. 50 0.323 >50% lysis
6 IIa-2 10 1.766 No lysis -
7 20 1.699 No lysis
8 25 0.801 No lysis
9 30 0.742 No lysis
10 50 0.457 <50% lysis
11 IIa-3 10 0.816 No lysis 50µg
12 20 0.718 No lysis
13 25 0.544 No lysis
14 30 0.453 <50% lysis
15 50 0.352 50% lysis
16 IIb-1 10 0.634 No lysis 50µg
17 20 0.443 <50% lysis
18 25 0.418 <50% lysis
19 30 0.403 <50% lysis
20 50 0.399 50% lysis
21 IIb-3 10 0.266 >50% lysis -
22 20 0.252 >50% lysis
23 25 0.252 >50% lysis
24 30 0.248 >50% lysis
25 50 0.191 >50% lysis
26 IIb-5 10 1.521 No lysis -
27 20 0.825 No lysis
28 25 0.694 No lysis
29 30 0.468 No lysis
30 50 0.411 <50% lysis
96 Control 00 0.688 No lysis -

Table 3: Results for anticancer activity on Hep 3b cell line

S.No. Sample Concentration (µg) Absorbance Results as observed IC50 (µg)
1. IIIa-1 10 0.397 >50% lysis <10µg
2. 20 0.388 >50% lysis
3. 25 0.325 >50% lysis
4. 30 0.287 >50% lysis
5. 50 0.281 >50% lysis
6 IIIb-1 10 0.721 <50% lysis 20µg
7 20 0.570 50% lysis
8 25 0.488 >50% lysis
9 30 0.423 >50% lysis
10 50 0.359 >50% lysis
11 IIIa-2 10 0.606 <50% lysis 20µg
12 20 0.527 50% lysis
13 25 0.303 >50% lysis
14 30 0.299 >50% lysis
15 50 0.260 >50% lysis
16 IIIb-2 10 0.822 <50% lysis 25µg
17 20 0.672 <50% lysis
18 25 0.585 50% lysis
19 30 0.571 50% lysis
20 50 0.486 >50% lysis
21 IIIa-3 10 0.698 <50% lysis 20µg
22 20 0.558 50% lysis
23 25 0.425 >50% lysis
24 30 0.360 >50% lysis
25 50 0.335 >50% lysis
26 IIIb-3 10 0.995 No lysis 25µg
27 20 0.613 <50% lysis
28 25 0.591 50% lysis
29 30 0.477 >50% lysis
30 50 0.472 >50% lysis
96 Control 00 1.079 No lysis -

Spectral data of 4-hydroxy-1-methyl-3-(1-(phenylimino)ethyl)quinolin-2(1H)-one. (IIIb-1)

IR (KBr, cm-1): 3078.39, (aromatic C-H); 2983.88, 2852.93 (aliphatic C-H); 1655.29(-C=N);1612.49 (-C=O cyclic amide).

Spectral data of 3-(1-((4-chlorophenyl)imino)ethyl)-4-hydroxy-1-methylquinolin-2(1H)-one. (IIIb-2)

IR (KBr, cm-1): 3078.39 (aromatic C-H); 2941.44, 2924.09 (aliphatic C-H); 1651.07 (-C=N);1563.60 (C=O cyclic amide).

Anticancer activity

The 4-hydroxy-3-(3-substituted-1-(substituted amino)propyl-1-phenyl/methylquinolin-2(1H)-one derivatives and 4-hydroxy-1-phenyl/methyl-3-(1-substituted imino)methyl quinolin-2(1H)-one derivatives were tested for their in vitro anticancer activity against K562 and Hep 3b cell lines by MTT assay method and the results are presented in table 2 and table 3.

DISCUSSION

The synthetic routes of the compounds are outlined in scheme-1. The compounds were satisfactorily characterized by IR and NMR spectral data. The presence of–C=N stretch between 1660-1640 cm-1 in the IR spectra of compounds from series IIa/IIb and IIIa/IIIb and also the presence of signals such as two triplets at δ 4.13 and 2.29 respectively for eight protons of morpholine substituent in 1H NMR spectrum of compound IIb-1; and singlet at 16.35 for one proton of–OH,multiplet at 8.20-6.51 for thirteen aromatic protonsand singlet at 2.2 for three protons of methyl group in 1H NMR spectrum of compoundIIIa-2 confirmed the synthesis of the derivatives. Similarly, results from the 13C NMR spectra and mass spectra of the compounds also proved the completion of reactions.

Selected compounds from the IIa/IIb series were tested for their in vitroanticancer activity against K562 cell line and those from the IIIa/IIIb series were evaluated for their in vitroanticancer activity against Hep 3b cell line. Compound IIa-1 (R=-C6H5 and R1=morpholine; R2=C6H5-NH-) showed the least IC50 value of 20µg and thus was the most potent compound againstK562 cell line. Compounds IIa-3 and IIb-1 had moderate potencies with an IC50 value of 50µg. The compounds IIa-2, IIb-3 and IIb-5 showed no cell lysis and were inactive. When evaluated for in vitroanticancer activity against Hep 3b cell line, all of the tested derivatives from IIIa/IIIb series exhibited cell lysis. The compound IIIa-1 (R=-C6H5 and R3=C6H5-NH-) was found to be most cytotoxic with an IC50 of less than 10µg. The compounds IIIb-2, IIIb-3 (IC50 value of 25µg) and IIIb-1, IIIa-2, IIIa-3 (IC50 value of 20µg) were found to be moderately potent.

CONCLUSION

The proposed method for the synthesis of novel quinolin-2-one derivatives is convenient and gives agood yield. Some of the synthesised compounds showed significant in vitro anticancer activity against K562 and Hep 3b cell lines. Compound IIa-1 (R=-C6H5; R1= morpholine; R2= C6H5-NH-) exhibited most potent activity against K562 cell lines. Compound IIIa-1 (R=-C6H5; R3= C6H5-NH-) was proved to be the most cytotoxic compound among the other derivatives against Hep 3b cell lines.

ACKNOWLEDGEMENT

We are thankful to the authorities of Sophisticated Analytical Instrumentation Facility, Panjab University, Chandigarh, for providing the facilities of spectral analysis such as 1H NMR, 13C NMR and mass. Our sincere gratitude is directed to Dr. Kishore Bhat, Professor and Head, Department of Microbiology, Maratha Mandal’s NGH Institute of Dental Sciences and Research Centre, Belgaum, Karnataka for providing the biological activity facility to carry out the anticancer activity.

AUTHORS CONTRIBUTION

Ms. Saili S. Desai (Departmentof Pharmaceutical Chemistry, P. E. S.’s Rajaram and Tarabai Bandekar College of Pharmacy, Farmagudi, Ponda-Goa) was in charge of the synthetic benchwork. Mr. Rudrax N. S. Priolkar (Departmentof Pharmaceutical Chemistry, P. E. S.’s Rajaram and Tarabai Bandekar College of Pharmacy, Farmagudi, Ponda-Goa) and Mr. Harshank A. Naik Karmali (DepartmentofPharmaceutical Chemistry, P. E. S.’s Rajaram and Tarabai Bandekar College of Pharmacy, Farmagudi, Ponda-Goa) were responsible for interpretation of the spectra. Mr. Prabhav D. Ambe (Departmentof Pharmaceutical Chemistry, P. E. S.’s Rajaram and Tarabai Bandekar College of Pharmacy, Farmagudi, Ponda-Goa) and Mr. B. S. Biradar (Departmentof Pharmacology, P. E. S.’s Rajaram and Tarabai Bandekar College of Pharmacy, Farmagudi, Ponda-Goa) assisted in the anticancer activity studies. Dr. S. N. Mamle Desai (Departmentof Pharmaceutical Chemistry, P. E. S.’s Rajaram and Tarabai Bandekar College of Pharmacy, Farmagudi, Ponda-Goa) is the research guide and supervised the overall research work.

CONFLICT OF INTERESTS

Declared none

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