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New pyrimidine derivatives: Synthesis,


antitumor and antioxidant evaluation

Article in International Journal of Pharmacy and Technology · April 2015

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Manal M. Anwar* et al. International Journal Of Pharmacy & Technology

ISSN: 0975-766X
CODEN: IJPTFI
Available Online through Research Article
www.ijptonline.com
NEW PYRIMIDINE DERIVATIVES: SYNTHESIS, ANTITUMOR AND
ANTIOXIDANT EVALUATION
Eman R. Kotb1, Eman M.H. Morsy1, Manal M. Anwar2*, Eman M. Mohi El-Deen2, Hanem , M. Awad3
1
Photochemistry Department, National Research Centre, Dokki, Giza, Cairo, Egypt.
2
Therapeutical Chemistry Department, National Research Centre, Dokki, Giza, Cairo, Egypt.
3
Department of Tanning Materials and Leather Technology, National Research Centre, Dokki, Cairo, Egypt.
Email: manal.hasan52@live.com
Received on 15-06-2015 Accepted on 07-07-2015

Abstract:

This study represents the synthesis of new derivatives of pyrimidine nucleus fused or conjugated with various

heteroaryl ring systems. Some of the new compounds were evaluated as antitumor and antioxidant agents. The results

indicated that the derivatives 9, 5b produced approximate equipotent antitumor activity to that of doxorubicin (%

growth inhibition; 75-56% respectively) against human liver (HepG2) and colorectal (HCT-116) carcinoma cell lines.

On the other hand, the antioxidant evaluation demonstrated strong scavenging activity of the tested derivatives

against the DPPH radicals. They exhibited more potency than rutin and ascorbic acid of IC50; 13.9-33.4 µM.

Keywords: thiopyrimidine, thiazolo[3,2-a]pyrimidine, antitumor, antioxidant activity.

Introduction

Pyrimidine heterocyclic core has a great value in medicinal chemistry since it comprises the base for thiamine, uracil

and cytosine nitrogen bases which are the building blocks of the nucleic acids [1,2]. Furthermore, pyrimidine

derivatives have registered their importance in the development of various pharmaceuticals of broad spectra of

therapeutical activities such as: anti-microbial [3], anti-viral, anti- HIV [4,5], anti-tubercular [6,7], anti-malarial [8,9],

analgesic, anti-inflammatory [10,11], diuretic [12], cardiovascular [13,14], hypnotic for the nervous system [15,16]

and antioxidant [17,18].

Other pyrimidine derivatives are considered as antagonists of calcium-sensing receptor [19] and the human A2A

adenosine receptor [20]. In addition, various drugs containing pyrimidine nucleus were synthesized and used as

anticancer agents like 5-Fluorouracil (5-FU), Tegafur and Thioguanine [21] (Fig. 1).

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Manal M. Anwar* et al. International Journal Of Pharmacy & Technology

Fig. (1): Pyrimidine derivatives as anticancer agents.

Moreover, it was documented that many fused pyrimidine analogues were reported to be inhibitors of tyrosine kinase

and cyclin-dependent kinases, which are involved in mediating the transmission of mitogenic signals and numerous

other cellular events, including, cell proliferation, migration, differentiation, metabolism, and immune responses

[22,23].

Cancer is one of the most dreadful diseases in the world. Despite the great development of the basic and clinical

research, which increased the cure rates for a number of malignancies, cancer remains the second leading cause of

human mortality in developing and developed countries. Although chemotherapy is the mainstay of cancer therapy,

the use of available chemotherapeutics is often limited mainly due to the undesirable side effects. Also, drug

resistance constitutes lack of response to many chemically and mechanically unrelated anticancer agents by cancer

cells. It is one of the main reasons for failure of chemotherapy and recurrence of the disease or even death may occur.

Therefore, the development of new drugs with more effective treatment strategies for cancer with well-defined

pharmacokinetic properties always remains an important and challenging goal in medicinal chemistry [24-26].

At the same time, reactive oxygen species (ROS), such as superoxide radicals, hydroxyl (OH) radicals and peroxyl

radicals, are natural byproducts of the normal metabolism of oxygen in living organisms with important roles in cell

signaling. However, excessive amounts of ROS may be a primary cause of biomolecular oxidation and may result in

significant damage to cell structure, DNA, protein, and lipid contributing to various diseases, such as cancer, stroke,

diabetes and degenerative processes associated with ageing. Minimizing oxidative damage may be an important

approach to the primary prevention or treatment of these diseases. Antioxidants are important inhibitors of lipid

peroxidation not only for food protection but also as a defense mechanism of living cells against oxidative damage

since they may stop the free-radical formation, or interrupt an oxidizing chain reaction [27-29].

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Manal M. Anwar* et al. International Journal Of Pharmacy & Technology
In view of the above facts and in continuation of our previous efforts in the field of synthesis of novel anticancer

chemotherapeutics [30-33], the target in this study was to synthesize new hybrid compounds having the pyrimidine

moiety fused or conjugated with different aromatic/heterocylic/side chains of documented cytotoxic potency against

several cancer cell lines such as: naphthalene, benzenesulfonamide, thiazolidine, isoxzole, pyrazoline, isoindoline,

pyrrole, chloroethoxy ethyl thio and methyl mannich side chains [26,30,34-40]. Some of the new compounds were

selected as representative examples to evaluate their antitumor activity against human liver (HepG-2) and colorectal

(HCT116) carcinoma cell lines using doxorubicin as a reference drug. Moreover, the free-radical scavenging

properties were also screened for the same derivatives using rutin and vitamin C as reference standards.

Materials and Methods

Chemistry

Regents were purchased from Acros (Geel, Belgium) and Aldrich (St. Louis, MO, USA) and were used without

purification. Melting points were determined by open capillary tubes on an electrical melting point apparatus and are

uncorrected. Nuclear Magnetic Resonance (1H NMR and 13


C NMR) spectra were taken on Varian Mercury (500

MHz) spectrometer (Varian, UK) at National Research Centre (NRC), Cairo, Egypt. Chemical shifts (δ) were

expressed in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard. The splitting pattern

abbreviations are as follows: s, singlet; br, broad singlet; d, doublet; t, triplet; q, quadruplet; m, multiplet. The

exchangeable protons (OH and NH) were verified by D2O exchange. Mass spectra were recorded at 70 eV on EI Ms-

QP 1000 EX (Shimadzu, Japan), at the Faculty of Science, Cairo University, Egypt, presented as m/z. IR spectra were

recorded on Perkin-Elmer 1650 spectrophotometer, at NRC by means of KBr pellets of the compounds. Elemental

analyses were carried out using Vario El-Mentar apparatus (Shimadzu, Japan) at NRC. The values found were within

± 0.4% of the theoretical values. The steps of the chemical reactions and purity of the synthesized products were

confirmed on precoated thin layer chromatographic plates (silica gel 60 F254, Merck) using a mixture of chloroform

and methanol (5 μ 1, v/v) as an eluent. The chromatograms were visualized under iodine vapor/UV light at β54 nm

General procedure for the synthesis of compounds 1a,b:

A mixture of urea and/or thiourea (0.01 mol), 1-naphthalenaldehyde (1.5 g; 0.01 mol) and acetylacetone (1.0 g; 0.01

mol) in ethanolic KOH solution (2 g KOH in 100 mL ethanol) was refluxed for 8h. The reaction solution was allowed

to cool and the resultant precipitate was collected by filtration, washed with water, dried and recrystallized from

acetic acid to give the corresponding derivatives 1a,b.

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Manal M. Anwar* et al. International Journal Of Pharmacy & Technology
1-(6-Methyl-4-(naphthalen-1-yl)-2-oxo-1,2,3,4-tetrahydropyrimidin-5-yl)ethanone (1a)

Yield: 80%, mp. 210-202 °C, IR (KBr) υ (cm-1): 3250, 3165 (2NH), 1730, 1703 (2C=O). 1H NMR (DMSO-d6, 500

MHz, δ ppm)μ 1.7γ (s, γH, CH3), 2.35 (s, 3H, -COCH3), 5.15 (s, 1H, pyrimidine- H4), 6.61, 6.65 (2s, 2H, 2NH,

exchangeable with D2O), 7.20-7.85 (m, 7H, Ar-H). 13C NMR (DMSO-d6, 500 MHz) δ (ppm)μ 17.4 (CH3), 22.5 (-CO-

CH3), 51.1 (pyrimidine-C4), 117.0, 123.9, 125.2, 125.4, 126.0, 126.2, 126.5, 128.3, 132.5, 133.4, 134.0, 150.0 (Ar-C,

pyrimidine-C), 156.0, 178.2, (2C=O). MS (EI) m/z: 280 (M+, 70%). Anal. Calcd. for C17H16N2O2 (280.32): C, 72.84;

H, 5.75; N, 9.99. Found: C, 72.41; H, 5.42; N, 10.21.

1-(6-Methyl-4-(naphthalen-1-yl)-2-thioxo-1,2,3,4-tetrahydropyrimidin-5-yl)ethanone (1b)

Yield: 85%, mp. 210-β1β °C, IR (KBr) υ (cm-1): 3200, 3115 (2NH), 1703 (C=O), 1224 (C=S). 1H NMR (DMSO-d6,

500 MHz, δ ppm)μ 1.70 (s, γH, CH3), 2.32 (s, 3H, -COCH3), 2.25, 2.50 (2s, 2H, 2NH, exchangeable with D2O), 5.10

(s, 1H, pyrimidine-H4), 7.10-7.69 (m, 7H, Ar-H). 13C NMR (DMSO-d6, 500 MHz) δ (ppm)μ 18.0 (CH3), 22.5 (-CO-

CH3), 51.5 (pyrimidine-C4), 123.9, 125.2, 125.4, 126.0, 126.2, 126.5, 128.3, 132.5, 133.4, 134.0, 150.0 (Ar-C,

pyrimidine-C), 156.0, 196.1 (C=O, C=S). MS (EI) m/z: 296 (M+, 70%). Anal. Calcd. for C17H16N2OS (296.39): C,

68.89; H, 5.44; N, 9.45; S, 10.82. Found: C, 68.41; H, 5.22; N, 10.56; S, 11.13.

General procedure for the synthesis of 6-Acetyl-7-methyl-5-(naphthalen-1-yl)-2H-thiazolo[3,2-a]pyrimidin-

3(5H)-one (2)

The pyrimidine-2-thioxo derivative 1b (2.8 g; 0.01 mol) and bromoacetic acid (1.3 g; 0.01 mol) were dissolved in a

mixture solution of acetic acid (30 mL)/acetic anhydride (15 mL) containing anhydrous sodium acetate (2 g). The

reaction mixture was refluxed for 7h. After the reaction completion, the solution mixture was cooled, poured onto

cold water. The formed product was washed several time with water, filtered, dried and recrystallized from acetic

acid to give the target compound 2.

Yield: 60%, mp. 240-β4β °C, IR (KBr) υ (cm-1): 1730, 1723 (2C=O), 1638 (C=N). 1H NMR (DMSO-d6, 500 MHz, δ

ppm): 1.75 (s, 3H, CH3), 2.33 (s, 3H, -COCH3), 3.78 (s, 2H, CH2, thiazolidine ring), 5.15 (s, 1H, pyrimidine-H4),

7.10-7.77 (m, 7H, Ar-H). 13


C NMR (DMSO-d6, 500 MHz, δ ppm)μ 18.7 (CH3), 22.6 (-CO-CH3), 33.6 (-CH2,

thiazolidine ring), 51.8 (pyrimidine-C4), 117.0, 123.9, 125.5, 125.7, 126.0, 126.7, 127.5, 128.9, 133.5, 133.9, 135.0,

145.3, 150.0 (Ar-C, pyrimidine-C), 157.0, 176.2 (2C=O). MS (EI) m/z: 336 (M+, 70%). Anal. Calcd. for

C19H16N2O2S (336.41): C, 67.84; H, 4.79; N, 8.33; S, 9.53. Found: C, 68.20; H, 4.54; N, 8.72; S, 9.12.

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Manal M. Anwar* et al. International Journal Of Pharmacy & Technology
General procedure for the synthesis of (Z)-6-acetyl-2-(4-chlorobenzylidene)-5-methyl-7-(naphthalen-1-yl)-2,7-

dihydro-1H-thiazolo[3,2-a]pyrimidin-1-one (3)

A mixture of the pyrimidine-2-thioxo derivative 1b (2.8 g; 0.01 mol), bromoacetic acid (1.3 g; 0.01 mol), p-

chlorobenzaldehyde (1.4 g; 0.01 mol), anhydrous sodium acetate (1 g) in a mixture of acetic acid (30 mL)/acetic

anhydride (15 mL) was heated under reflux for 12h. The reaction mixture was cooled to room temperature and

poured onto cold water with vigorous stirring. The precipitated solid was filtered under suction, washed with cold

water and recrystallized from acetic acid to obtain the required product 3.

Yield: 70%, mp. 257-β5λ °C, IR (KBr) υ (cm-1): 1745, 1705 (2C=O), 1638 (C=N). 1H NMR (DMSO-d6, 500 MHz,

δ ppm)μ 1.75 (s, γH, CH3), 2.35 (s, 3H, -COCH3), 5.52 (s, 1H, pyrimidine- H4), 7.20 (s, 1H, exocyclic vinylic-H),

7.35-7.79 (m, 11H, Ar-H). MS (EI) m/z: 458 (M+, 70%); 460 (M+ +2, 23%). Anal. Calcd. for C26H19ClN2O2S

(458.96): C, 68.04; H, 4.17; N, 6.10; S, 6.99. Found: C, 68.31; H, 4.47; N, 5.85; S, 7.35.

General procedure for the synthesis of 6-Acetyl-2,7-dimethyl-5-(naphthalen-1-yl)-2H-thiazolo[3,2-a]pyrimidin-

3(5H)-one (4)

The derivative 1b (2.8 g; 0.01 mol) and 2-bromopropionic acid (1.5 g; 0.01 mol) were dissolved in a mixture solution

of acetic acid (30 mL)/acetic anhydride (15 mL) containing anhydrous sodium acetate. (2 g). The reaction mixture

was refluxed for 7h. Upon the reaction completion, the solution mixture was cooled, poured onto cold water. The

formed precipitate was washed several times with water, filtered, dried and recrystallized from acetic acid to give the

title compound 4.

Yield: 65%, mp. 248-β50 °C, IR (KBr) υ (cm-1): 1740, 1700 (2C=O), 1640 (C=N). 1H NMR (DMSO-d6, 500 MHz, δ

ppm): 1.48, (d, 3H, J= 7.6 Hz, CH3), 1.73 (s, 3H, CH3), 2.32 (s, 3H, -COCH3), 3.70-3.74 (q, 1H, -CH, thiazolidine

ring), 5.60 (s, 1H, pyrimidine-H4), 7.12-7.77 (m, 7H, Ar-H). 13


C NMR (DMSO-d6, 500 MHz, δ ppm)μ 16.5, 17.5,

22.0 (3CH3), 42.6 (-CH, thiazolidine ring), 51.1 (pyrimidine-C4), 123.6, 125.1, 125.7, 126.3, 127.5, 128.5, 132.5,

133.9, 135.4, 143.3, 149.5.0 (Ar-C, pyrimidine-C), 168.0, 171.01 (2C=O). MS (EI) m/z: 350 (M+, 20%). Anal. Calcd.

for C20H18N2O2S (350.43): C, 68.55; H, 5.18; N, 7.99; S, 9.15. Found: C, 68.21; H, 4.88; N, 8.31; S, 9.00.

General procedure for the synthesis of compounds 5a-c:

A mixture of compound 2 (3.31 g; 0.01 mol) and the appropriate monosaccharides namely: D-arabinose, D-glucose

and D-mannose in absolute ethanol in the presence of few drops of glacial acetic acid was refluxed for 6 h. The

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Manal M. Anwar* et al. International Journal Of Pharmacy & Technology
reaction mixture was cooled and the formed precipitate was filtered, dried and recrystallized from ethanol to obtain

the target compounds 5a-c, respectively.

(Z)-6-Acetyl-5-methyl-7-(naphthalen-2-yl)-2-((2R,3S,4R)-2,3,4,5-tetrahydroxy pentylidene)-2,7-dihydro-1H-

thiazolo[3,2-a]pyrimidin-1-one (5a)

Yield: 68%; m.p.: 232~234°C. IR (KBr) υ (cm-1): 3529-3442 (br. OH), 1733, 1720 (2C=O), 1640 (C=N). 1H NMR

(DMSO-d6, 500 MHz, δ ppm)μ 1.7γ (s, γH, CH3), 2.30 (s, 3H, -COCH3), 3.30-3.42 (m, 3H, pentylidene side chain),

3.70-3.78 (m, 2H, CH2OH), 4.22-5.00 (m, 4H, 4OH, D2O exchangeable), 5.50 (s, 1H, pyrimidine-H4), 5.82 (m, 1H,

exocyclic vinylic-H), 7.12-7.67 (m, 7H, Ar-H). MS (EI) m/z: 468 (M+, 24%). Anal. Calcd. for C24H24N2O6S (468.52):

C, 61.52; H, 5.16; N, 5.98; S, 6.84. Found: C, 61.42; H, 4.85; N, 5.63; S, 6.40.

(E)-6-acetyl-5-methyl-7-(naphthalen-2-yl)-2-((2S,3R,4R,5R)2,3,4,5,6- pentahydroxy hexylidene)-2,7-dihydro-

1H-thiazolo[3,2-a]pyrimidin-1-one (5b)

Yieldμ 65%; m.p.μ β54~β56°C. IR (KBr) υ (cm-1): 3545-3450 (br. OH), 1729, 1725 (2C=O), 1630 (C=N). 1H NMR

(DMSO-d6, 500 MHz, δ ppm)μ 1.75 (s, 3H, CH3), 2.30 (s, 3H, -COCH3), 3.30-3.42 (m, 4H, hexylidene side chain),

3.81-3.89 (m, 2H, CH2OH), 4.50-5.00 (m, 5H, 5OH, D2O exchangeable), 5.52 (s, 1H, pyrimidine-H4), 5.62 (m, 1H,

exocyclic vinylic-H), 7.35 -7.74 (m, 7H, Ar-H). MS (EI) m/z: 498 (M+, 30%). Anal. Calcd. for C25H26N2O7S

(498.55): C, 60.23; H, 5.26; N, 5.62; S, 6.43. Found: C, 60.62; H, 5.51; N, 5.31; S, 6.10.

(E)-6-acetyl-5-methyl-7-(naphthalen-2-yl)-2-((2S,3S,4S,5S)-2,3,4,5,6-pentahydroxy hexylidene)-2,7-dihydro-

1H-thiazolo[3,2-a]pyrimidin-1-one (5c)

Yieldμ 67%; m.p.μ β5β~β54°C. IR (KBr) υ (cm-1): 3550-3453 (br. OH), 1729, 1723 (2C=O), 1637 (C=N). 1H NMR

(DMSO-d6, 500 MHz, δ ppm)μ 1.75 (s, γH, CH3), 2.25 (s, 3H, -COCH3), 3.27-3.38 (m, 4H, hexylidene side chain),

3.80-3.90 (m, 2H, CH2OH), 4.55-5.07 (m, 5H, 5OH, D2O exchangeable), 5.61 (s, 1H, pyrimidine H-4), 5.60 (m, 1H,

exocyclic vinylic-H), 7.12-7.81 (m, 7H, Ar-H). MS (EI) m/z: 498 (M+, 35%). Anal. Calcd. for C25H26N2O7S (498.55):

C, 60.23; H, 5.26; N, 5.62; S, 6.43. Found: C, 60.62; H, 5.51; N, 5.31; S, 6.10.

General procedure for the synthesis of compounds 6,7:

A mixture of the compound 3 (4.5 g; 0.01 mol) and hydrazine hydrate 98% (0.02 mol) and/or phenyl hydrazine (0.01

mol) in ethanol (30 mL) was refluxed for 7h. The solution was cooled and the formed precipitate was filtered, dried

and recrystallized from dioxane to give the desired products 6,7 respectively.

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1-(3-(4-Chlorophenyl)-6-methyl-8-(naphthalen-1-yl)-2,3,3a,8-tetrahydropyrazole [3',4':4,5] thiazolo [3,2-

a]pyrimidin-7-yl)ethanone (6)

Yield: 70%, mp. 240-β4β °C, IR (KBr) υ (cm-1): 3346 (NH), 1705 (C=O), 1640 (C=N). 1H NMR (DMSO-d6, 500

MHz, δ ppm)μ 1.68 (s, γH, CH3), 2.12 (s, 3H, -COCH3), 3.30, 4.42 (2d, J= 6.9 Hz, 2H, pyrazoline-H3, H4), 5.60 (s,

1H, pyrimidine-H4), 7.12-7.72 (m, 11H, Ar-H), 7.72 (s, 1H, NH, exchangeable with D2O). MS (EI) m/z: 472 (M+,

30%), 474 (M+ +2, 9%). Anal. Calcd. for C26H21ClN4OS (472.99): C, 66.02; H, 4.48; N, 11.85; S, 6.78. Found: C,

66.21; H, 4.88; N, 11.51; S, 6.50.

1-(3-(4-chlorophenyl)-6-methyl-8-(naphthalen-1-yl)-2-phenyl-2,8-dihydropyrazolo [3',4':4,5] thiazolo [3,2-a]

pyrimidin-7-yl) ethanone (7)

Yield: 60%, mp. 248-β50 °C, IR (KBr) υ (cm-1): 1703 (C=O), 1638 (C=N). 1H NMR (DMSO-d6, 500 MHz) δ (ppm)μ

1.75 (s, 3H, CH3), 2.41 (s, 3H, -COCH3), 3.30, 4.42 (2d, J= 6.9 Hz, 2H, pyrazoline-H3, H4), 5.23 (s, 1H, pyrimidine-

H4), 7.12-8.00 (m, 16H, Ar-H). MS (EI) m/z: 549 (M+, 35%), 551 (M+ +2), 12%). Anal. Calcd. for C32H25ClN4OS

(549.09): C, 70.0; H, 4.59; N, 10.20; S, 5.84. Found: C, 70.45; H, 4.78; N, 10.51; S, 6.10.

General procedure for the synthesis of 1-(3-(4-chlorophenyl)-6-methyl-8-(naphthalen-1-yl)-8H-isoxazolo

[3',4':4,5] thiazolo [3,2-a]pyrimidin-7-yl)ethanone (8)

A mixture of compound 3 (4.5 g; 0.01 mol) and hydroxylamine hydrochloride (0.7 g, 0.01 mol) in ethanolic sodium

hydroxide (5%, 20 mL) was refluxed for 10h. The reaction mixture was cooled, poured onto ice/cold water and

acidified by diluted hydrochloric acid. The formed precipitate was filtered, dried and recrystallized from dioxane to

give the target compound 8.

Yield: 75%, mp. 250-β5β °C, IR (KBr) υ (cm-1): 1710 (C=O), 1640 (C=N). 1H NMR (DMSO-d6, 500 MHz, δ ppm)μ

1.81 (s, 3H, CH3), 2.36 (s, 3H, -COCH3), 5.23 (s, 1H, pyrimidine-H4), 7.12-8.00 (m, 11H, Ar-H). MS (EI) m/z: 471

(M +, 33%), 473 (M + +2, 10%). Anal. Calcd. for C26H18ClN3O2S (471.96): C, 66.17; H, 3.84; N, 8.90; S, 6.79. Found:

C, 66.51; H, 4.16; N, 9.32; S, 6.47.

General procedure for the synthesis of 2-((5-Acetyl-6-methyl-4-(naphthalen-1-yl)-1,2,3,4-tetrahydropyrimidin-

2-yl)thio)acetic acid (9)

A solution mixture of compound 1b (2.8 g; 0.01 mol) and chloroacetic acid (1.0 g, 0.01 mol) in ethanolic sodium

hydroxide (5%, 20 mL) was refluxed for 4h. After the reaction was completed, the reaction solution was poured onto

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Manal M. Anwar* et al. International Journal Of Pharmacy & Technology
cold water and the formed precipitate was filtered, dried and recrystallized from the ethanol to get the title compound

9.

Yield: 60%, mp. 192-1λ4 °C, IR (KBr) υ (cm-1): 3426 (OH), 3230 (NH), 1730, 1710 (2C=O). 1H NMR (DMSO-d6,

500 MHz) δ (ppm)μ 1.7γ (s, γH, CH3), 2.20 (s, 1H, NH, exchangeable with D2O), 2.36 (s, 3H, -COCH3), 3.45 (s, 2H,

CH2), 5.15 (s, 1H, pyrimidine-H4), 7.12-7.77 (m, 7H, Ar-H), 11.40 (s, 1H, OH, exchangeable with D2O). 13C NMR

(DMSO-d6, 500 MHz, δ ppm)μ 18.5, ββ.7 (βCH3), 31.5 (CH2), 50.5 (pyrimidine-C4), 123.4, 125.8, 126.0, 126.3,

127.5, 128.1, 132.0, 133.7, 135.4, 143.3, 150.1 (Ar-C), 176.0, 195.5 (2C=O). MS (EI) m/z: 354 (M +, 50%). Anal.

Calcd. for C19H18N2O3S (354.42): C, 64.39; H, 5.12; N, 7.90; S, 9.05. Found: C, 64.12; H, 4.83; N, 7.54; S, 9.31.

General procedure for the synthesis of 1-(2-((2-(2-Chloroethoxy) ethyl) thio)-4-methyl-6-(naphthalen-1-yl)-1,6-

dihydropyrimidin -5-yl) ethanone (10)

The compound 1b (2.8 g; 0.01 mol) was dissolved in ethyl alcohol (20 mL) containing potassium hydroxide (0.56 g;

0.01 mol) and the solution mixture was heated with continuous stirring at 60 °C for 3h. Then, bis(chloroethyl) ether

(1.43 g; 0.01 mol) was added and the reaction mixture was continued heated under reflux for further 3h.

Upon reaction completion, the excess solvent was evaporated under reduced pressure and the obtained residue was

washed with cold water several times, filtered, dried and recrystallized from ethanol to give the desired product 10.

Yield: 62%, mp. 126-1β8 °C, IR (KBr) υ (cm-1): 3206 (NH), 1730 (C=O). 1H NMR (DMSO-d6, 500 MHz, δ ppm)μ

1.65 (s, 3H, CH3), 2.21 (s, 1H, NH, exchangeable with D2O), 2.34 (s, 3H, -COCH3), 2.71 ( t, J= 2.6 Hz, 2H, S-CH2-),

3.50, 3.91 (2t, J= 2.9 Hz, 2.8 Hz, 4H, O(CH2)2), 3.60 (t, J= 2.7 Hz, 2H, Cl-CH2-), 5.15 (s, 1H, pyrimidine-H4), 7.12-

7.97 (m, 7H, Ar-H). MS (EI) m/z: 402 (M +, 100%), 404 (M + +2, 30%). Anal. Calcd. for C21H23ClN2O2S (402.94): C,

62.60; H, 5.75; N, 6.95; S, 7.96. Found: C, 62.94; H, 5.83; N, 6.57; S, 7.61.

General procedure for the synthesis of 1-(4-Methyl-6-(naphthalen-1-yl)-2-(piperidin-1-yl)-1,6-

dihydropyrimidin-5-yl)ethanone (11)

A mixture solution of compound 1b (2.8 g; 0.01 mol) and piperidine (0.1 g; 0.01 mol) in methyl alcohol (20 mL) was

refluxed for 5h. The resultant solid was collected by filtration, dried and recrystallized from ethanol to give the target

product 11.

Yield: 60%, mp. 170-17β °C, IR (KBr) υ (cm-1): 3226 (NH), 1703 (C=O), 3059 (CH-Ar), 2941 (CH, alicylic). 1H

NMR (DMSO-d6, 500 MHz, δ ppm)μ 1.55-1.65 (m, 6H, , 3CH2 of piperidine ring), 1.73 (s, 3H, CH3), 2.21 (s, 1H,

NH, exchangeable with D2O), 2.35 (s, 3H, -COCH3), γ.1β (m, 4H, α βCH2 of piperidine ring), 5.15 (s, 1H,

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pyrimidine-H4), 7.12-7.75 (m, 7H, Ar-H). 13C NMR (DMSO-d6, 500 MHz, δ ppm)μ 18.0 (CH3), 22.5 (-COCH3),

23.5, 25.4, 25.9 (3CH2, piperidine ring), 44.4 (-N(CH2)2, piperidine ring), 50.1 (pyrimidine-C4), 111.5, 123.5, 125.6,

126.5, 127.1, 127.5, 128.5, 131.0, 133.2, 134.4, 145.3, 150.6 (Ar-C, pyrimidine-C), 175.0 (C=O). MS (EI) m/z: 347

(M +, 43%). Anal. Calcd. for C22H25N3O (347.45): C, 76.05; H, 7.25; N, 12.09. Found: C, 76.47; H, 7.51; N, 12.42.

General procedure for the synthesis of 1-(2-Hydrazinyl-4-methyl-6-(naphthalen-1-yl)-1,6-dihydropyrimidin-5-

yl)ethanone (12)

A mixture of compound 1b (2.8 g; 0.01 mol) and hydrazine hydrate 98% (0.10 mL, 0.02 mol) in absolute ethanol (10

mL) was refluxed for 4h. The formed precipitate was filtered, dried and recrystallized from ethanol to give the title

compound 12.

Yield: 60%, mp. 238-β40 °C, IR (KBr) υ (cm-1): 3422, 3245, 3150 (NH2, NH), 1703 (C=O). 1H NMR (DMSO-d6,

500 MHz) δ (ppm)μ 1.75 (s, γH, CH3), 2.25, 2.29 (2s, 2H, 2NH, exchangeable with D2O), 2.32 (s, 3H, -COCH3), 4.51

(s, 2H, NH2), 5.10 (s, 1H, pyrimidine-H4), 7.10-7.80 (m, 7H, Ar-H). 13C NMR (DMSO-d6, 500 MHz) δ (ppm)μ 17.β

(CH3), 22.9 (-OCH3), 50.6 (C-6, pyrimidine ring), 115.5, 122.5, 124.6, 126.4, 126.9, 127.5, 128.1, 131.7, 132.5,

134.4, 142.5, 151.7 (Ar-C), 175.6 (C=O). MS (EI) m/z: 294 (M +, 100%). Anal. Calcd. for C17H18N4O (294.35): C,

69.37; H, 6.16; N, 19.03. Found: C, 69.04; H, 5.86; N, 19.43.

General procedure for the synthesis of compounds 13a,b:

To a solution of the hydrazinyl compound 12 (2.9 g; 0.01 mol) in glacial acetic acid (30 mL), phthalic anhydride

and/or dichloromaleic anhydride (0.01 mol) was added. The reaction solution was refluxed for 8h. Upon reaction

completion, the solution was poured onto ice/water and the formed precipitate was filtered, washed with water, dried

and recrystallized from dioxane to obtain the corresponding compounds 13a,b.

2-((5-Acetyl-4-methyl-6-(naphthalen-1-yl)-1,6-dihydropyrimidin-2-yl)amino) isoindoline-1,3-dione (13a)

Yield: 60%, mp. > γ00 °C, IR (KBr) υ (cm-1): 3256, 3216 (2NH), 1730, 1698 (3C=O). 1H NMR (DMSO-d6, 500

MHz, δ ppm)μ 1.70 (s, γH, CH3), 2.25, 3.20 (2s, 2H, 2NH, exchangeable with D2O), 2.32 (s, 3H, -COCH3), 5.10 (s,

1H, pyrimidine-H4), 7.20-8.20 (m, 11H, Ar-H). MS (EI) m/z: 424 (M +, 28%), 445 (M +
+2, 9%). Anal. Calcd. for

C25H20N4O3 (424.45): C, 70.74; H, 4.75; N, 13.20. Found: C, 70.41; H, 4.32; N, 13.17.

1-((5-Acetyl-4-methyl-6-(naphthalen-1-yl)-1,6-dihydropyrimidin-2-yl)amino)-3,4-dichloro-1H-pyrrole-2,5-

dione (13b)

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Yield: 69%, mp. 287-β8λ °C, IR (KBr) υ (cm-1): 3220, 3190 (2NH), 1737, 1703 (3C=O). 1H NMR (DMSO-d6, 500

MHz, δ ppm)μ 1.68 (s, γH, CH3), 2.00, 3.20 (2s, 2H, 2NH, exchangeable with D2O), 2.36 (s, 3H, -COCH3), 5.52 (s,

1H, pyrimidine–H4), 7.10-7.80 (m, 7H, Ar-H). MS (EI) m/z: 443 (M +, 27%). Anal. Calcd. for C21H16Cl2N4O3

(443.28): C, 56.90; H, 3.64; N, 12.64. Found: C, 56.48; H, 3.30; N, 12.32.

General procedure for the synthesis of 1-(2-Chloro-4-methyl-6-(naphthalen-1-yl)-1,6-dihydropyrimidin-5-

yl)ethanone (14)

A suspension of compound 1a (2.8 g, 0.01 mol) and PCl5 (0.5 g) in POCl3 (8 mL) was heated under reflux for 5h on a

water bath. After cooling, the reaction mixture was poured slowly on crushed ice (30 g) then neutralized with NaOH

solution. The solid formed was filtered, washed with cold water and dried to give the chloro derivative 14.

Yield: 75%, mp. 160-16β °C, IR (KBr) υ (cm-1): 3340 (NH), 1705 (C=O). 1H NMR (DMSO-d6, 500 MHz, δ ppm)μ

1.75 (s, 3H, CH3), 2.36 (s, 3H, -COCH3), 2.78 (s, 1H, NH, exchangeable with D2O), 5.22 (s, 1H, pyrimidine-H4),

7.10-7.72 (m, 7H, Ar-H). MS (EI) m/z: 298 (M +, 100%), 300 (M + +2, 30%). Anal. Calcd. for C17H15ClN2O (298.77):

C, 68.34; H, 5.06; N, 9.38. Found: C, 68.62; H, 5.37; N, 9.59.

General procedure for the synthesis of compounds 15a,b:

To a solution of the chloro derivative 14 (2.9 g; 0.01 mol) in absolute ethanol (30 mL) containing few drops of

triethylamine, the appropriate sulfonamide derivatives namely: sulfapyridine and/or sulfadiazine (0.01 mol) was

added. The reaction mixture was refluxed for 6h. Upon cooling, the formed solid was filtered, dried and recrystallized

from DMF/ethanol to get the title derivatives 15a,b, respectively.

4-((5-Acetyl-4-methyl-6-(naphthalen-1-yl)-1,6-dihydropyrimidin-2-yl)amino)-N-(pyridin-2-

yl)benzenesulfonamide (15a)

Yield: 65%, mp. 258-β60 °C, IR (KBr) υ (cm-1): 3345, 3339, 3330 (3NH), 1706 (C=O), 1396, 1176 (SO2). 1H NMR

(DMSO-d6, 500 MHz, δ ppm)μ 1.7γ (s, γH, CH3), 2.32 (s, 3H, -COCH3), 2.78, 3.20, 4.50 (3s, 3H, 3NH,

exchangeable with D2O), 5.03 (s, 1H, pyrimidine-H4), 6.80-8.00 (m, 15H, Ar-H). MS (EI) m/z: 511 (M +, 28%). Anal.

Calcd. for C28H25N5O3S (511.59): C, 65.74; H, 4.93; N, 13.69; S, 6.27. Found: C, 65.38; H, 4.50; N, 13.31; S, 6.01.

4-((5-Acetyl-4-methyl-6-(naphthalen-1-yl)-1,6-dihydropyrimidin-2-yl)amino)-N-(pyrimidin-2-

yl)benzenesulfonamide (15b)

Yield: 65%, mp. 240-β4β °C, IR (KBr) υ (cm-1): 3360, 3345, 3332 (3NH), 1705 (C=O), 1338, 1195 (SO2). 1H NMR

(DMSO-d6, 500 MHz, δ ppm)μ 1.70 (s, γH, CH3), 2.30 (s, 3H, -COCH3), 2.61, 3.32, 4.27 (3s, 3H, 3NH,

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exchangeable with D2O), 5.51 (s, 1H, pyrimidine-H4), 6.80-8.50 (m, 14H, Ar-H). MS (EI) m/z: 512 (M +, 28%). Anal.

Calcd. for C27H24N6O3S (512.58): C, 63.27; H, 4.72; N, 16.40; S, 6.26. Found: C, 62.81; H, 4.43; N, 16.12; S, 6.51.

General procedure for the synthesis of compounds 16a-c:

A solution of paraformaldehyde (0.90 g, 10 mmol) and the appropriate amines namely: N,N-dimethyl amine,

morpholine and/ p-toluidine (0.015 mol) was refluxed in absolute ethanol (20 mL) for 30 min till complete solubility

of para-formaldehyde. Then, a solution of the compound 1b (2.8 g; 0.01 mol) in absolute ethanol (10 mL) was added

to the previous mixture and refluxed for 8h. The product obtained upon cooling the reaction solution was filtered,

dried and recrystallized from ethanol to give the corresponding Mannich bases 16a-c.

1-(1,3-Bis((dimethylamino)methyl)-6-methyl-4-(naphthalen-1-yl)-2-thioxo-1,2,3,4- tetrahydropyrimidin-5-

yl)ethanone (16a)

Yield: 73%, mp. 247-249 °C, IR (KBr) υ (cm-1): 1700 (C=O), 1139 (C=S). 1H NMR (CDCl3-d6, 500 MHz, δ ppm)μ

1.73 (s, 3H, CH3), 2.34 (s, 3H, -COCH3), 2.74, 2.76 (2s, 6H, 6H, -2N(CH3)2), 4.51 (s, 4H, 2CH2), 5.21 (s, 1H,

pyrimidine-H4), 7.10-7.77 (m, 7H, Ar-H). MS (EI) m/z: 410 (M +, 43%). Anal. Calcd. for C23H30N4OS (410.58): C,

67.28; H, 7.36; N, 13.65; S, 7.81. Found: C, 67.61; H, 7.05; N, 13.81; S, 7.50.

1-(6-Methyl-1,3-bis(morpholinomethyl)-4-(naphthalen-1-yl)-2-thioxo-1,2,3,4-tetra hydropyrimidin-5-

yl)ethanone (16b)

Yield: 70%, mp. 245-247 °C, IR (KBr) υ (cm-1): 1709 (C=O), 1120 (C=S). 1H NMR (CDCl3-d6, 500 MHz, δ ppm)μ

1.75 (s, 3H, CH3), 2.24 (s, 3H, -COCH3), 2.62 (m, 4H, 4H, -2N(CH2)2, morpholine ring), 3.42 (m, 4H, 4H, -

2O(CH2)2, morpholine ring ), 4.54 (s, 4H, 2CH2), 5.25 (s, 1H, pyrimidine-H4), 7.10-7.79 (m, 7H, Ar-H). MS (EI) m/z:

494 (M+, 50%). Anal. Calcd. for C27H34N4O3S (494.65): C, 65.56; H, 6.93; N, 11.33; S, 6.48. Found: C, 65.21; H,

6.63; N, 11.81; S, 6.13.

1-(6-methyl-4-(naphthalen-1-yl)-2-thioxo-1,3-bis((p-tolylamino)methyl)-1,2,3,4-tetrahydro pyrimidin-5-

yl)ethanone (16c)

Yield: 73%, mp. 255-β57 °C, IR (KBr) υ (cm-1): 3365 (2NH), 1705 (C=O), 1135 (C=S). 1H NMR (CDCl3-d6, 500

MHz, δ ppm)μ 1.71 (s, γH, CH3), 2.26 (s, 3H, -COCH3), 2.29, 3.10 (2s, 2H, 2NH, exchangeable with D2O), 2.62 (s,

3H, 3H, -2CH3, p-toulidine ring), 4.50 (s, 4H, 2CH2), 5.53 (s, 1H, pyrimidine-H4), 7.23-7.83 (m, 15H, Ar-H). MS

(EI) m/z: 534 (M+, 46%). Anal. Calcd. for C27H34N4O3S (534.71): C, 74.12; H, 6.41; N, 10.48; S, 6.00. Found: C,

73.81; H, 6.32; N, 10.26; S, 6.47.

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Biological Methods

In-vitro antitumor evaluation

HepG-2 (Human liver carcinoma) and HCT116 (human colorectal carcinoma) cell lines were kindly supplied by

Applied Research Sector, VACSERA-Egypt and maintained in RPMI-1640 medium which was supplemented with

10% heat-inactivated FBS, 100U/ml penicillin and 100U/ml streptomycin. The cells were grown at 37°C in a

humidified atmosphere of 5% CO2. All experiments were conducted thrice in triplicate (n = 3). All the values were

represented as means ± SD.

MTT antitumor assay

The cytotoxic

ity activity against HepG2 and HCT-116 cancer cell lines was estimated using the 3-[4,5-dimethyl-2-thiazolyl)-2,5-

diphenyl-2H-tetrazolium bromide (MTT) assay, which is based on the cleavage of the tetrazolium salt by

mitochondrial dehydrogenases in viable cells [41,42]. Cells were dispensed in a 96 well sterile microplate (5 x 10 4

cells/well), and incubated at 37oC with 100 µM/ml of each tested compound or Doxorubicin (positive control) for 48

h in a serum free medium prior to the MTT assay. After incubation, media were carefully removed, 40 µL of MTT (5

mg/mL) were added to each well and then incubated for an additional 4 h. The purple formazan dye crystals were

solubilized by the addition of 200 µL of acidified isopropanol. The absorbance was measured at 570 nm using a

microplate ELISA reader (Biorad, USA). The relative cell viability was expressed as the mean percentage of viable

cells compared to the untreated control cells.

Statistical analysis

All experiments were conducted in triplicate (n = 3). All the values were represented as mean ± SD. Significant

differences between the means of parameters as well as IC50s were determined by probit analysis using SPSS

software program (SPSS Inc., Chicago, IL).

In-vitro antioxidant activity

1,1-Diphenyl-2-picryl hydrazyl (DPPH) and Roswell Park Memorial Institute (RPMI) 1640 medium were purchased

from Sigma Chem. Co. (St. Louis, MO, USA). Fetal bovine serum (FBS) and fetal calf serum (FCS) were purchased

from Gibco, UK. Dimethyl sulfoxide (DMSO) and methanol were of HPLC grade and all other reagents and

chemicals were of analytical reagent grade. Antioxidant activity of each compound and standards (ascorbic acid and

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rutin) was assessed based on the radical scavenging effect of stable DPPH free radical [βλ]. 10 l of each tested

compound or standard (from 0.0 to 100 M) was added to λ0 l of a 100 M methanolic solution of DPPH in a λ6-

well microtitre plate (Sigma-Aldrich Co., St. Louis, MO, US). After incubation in dark at 37°C for 30 min, the

decrease in absorbance of each solution was measured at 520 nm using an ELISA micro plate reader (Model 550,

Bio-Rad Laboratories Inc., California, USA). Absorbance of blank sample containing the same amount of DMSO and

DPPH solution was also prepared and measured. All experiments were carried out in triplicate. The scavenging

potential was compared with a solvent control (0% radical scavenging) and the standard compounds. Radical

scavenging activity was calculated by the following formula:

% Reduction of absorbance = [(AB - AA) / AB] x 100, where: AB – absorbance of blank sample and AA –

absorbance of tested compound (t = 30 min). The concentration of each compound required to scavenge 50% of

DPPH (IC50) was determined as well [43,44].

Results and discussion

Chemistry

The synthetic strategies adopted for constructing the target molecules are illustrated in Schemes 1-3. The structures of

the isolated products were evidenced by their spectral data together with elemental analyses. The starting materials,

6-methyl-4-(naphthalen-1-yl)-2-oxo/thioxo-1,2,3,4-tetrahydropyrimidine derivatives 1a,b were prepared in

quantitative yields by condensation of urea/thiourea with 1-naphthaldehyde and acetyl acetone in refluxing ethanolic

KOH solution based on the previously reported similar methods [45-48]. IR spectra of the products displayed in each

case the absorption bands at the region of 3250-3115 cm-1 due to the (NH) groups and at 1730-1703 cm_1 due to

(2C=O) in case of 1a, while 1b exhibited two bands at 1703 and 1224 cm_1 due to C=O and C=S groups,

respectively. 1H NMR spectra of the two products showed two singlet signals at the region δ 1.7γ-2.35 ppm due to

6H of CH3 and -COCH3 groups and another singlet at δ 5.15 ppm assignable to H-4 of pyrimidine ring, in addition to

the other signals of the molecules that appeared at their expected regions. At the same time, 13C NMR of 1a,b showed

two signals at δ 17.4, ββ.5 ppm corresponding to CH3 and COCH3, respectively, at δ 156.0, 178.β, 1λ6.1 ppm due to

C=O and C=S groups, besides the other expected signals of the other carbons of the two molecules. Condensation

reaction of the pyrimidine-2-thioxo derivative 1b with bromoacetic acid in refluxing acetic acid/acetic anhydride

solution containing sodium acetate anhydrous led to the formation of the thiazolo[3,2-a]pyrimidine derivative 2. IR

spectrum of compound 2 displayed two absorption bands at 1730, 1723 cm_1 due to the presence of the acetyl and the

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lactamic C=O groups. While its H NMR spectrum revealed four singlets at δ 1.75, β.γγ, γ.78, 5.15 ppm assigned to
1

the corresponding methyl, acetyl and CH2, H-5 of thiazolo[3,2-a]pyrimidine residue, in addition to multiplet signals

at δ 7.10-7.77 ppm due to Ar-H. Furthermore, the arylidene analogue 3 has been synthesized in a one pot multi-

component reaction [49,50] involving compound 1b, bromoacetic acid and p-chlorobenzaldehyde in the presence of

anhydrous sodium acetate in a mixture solution of acetic acid/acetic anhydride (Scheme 1). IR spectrum of

compound-3 revealed the presence of two absorption bands at 1745, 1705 cm_1 assignable to 2C=O. Its 1H NMR, in

addition to the expected signals due to the aromatic protons, exhibited four singlet signals at δ 1.75, β.γ5, 5.5β ppm

referred to the protons of methyl, acetyl and pyrimidine H-4, respectively. The Z configuration of the exocyclic C=C

bond was assigned on the basis of 1H NMR spectroscopy according to literature data for analogous 4-thiazolidinones

[51,52]. The methine proton, deshielded by the adjacent C=O, was detected at 7.20 ppm. Similarly, compound 1b

was allowed to react with bromopropionic acid, under the same conditions, in a refluxing solution of acetic

acid/acetic anhydride containing sodium acetate anhydrous to form 2,7-dimethyl thiazolo[3,2-a]pyrimidine analogue

4. 1H NMR spectrum of compound 4 showed in addition to the expected two methyl and aromatic signals of the

parent thiopyrimidine core, new douplet and quartet signals appeared at δ 1.48 and γ.70 ppm assigned to the methine
13
and methyl protons of the thiazolidine ring. C NMR spectrum of the same derivative displayed eighteen carbon

signals, the most important signals appeared at δ 16.5, 17.5, ββ.0, 4β.6 representing the carbons of βCH 3 of

thiopyrimidine ring and the carbons of CH3 and CH of the thiazolidine ring, respectively. The thiazolo[3,2-

a]pyrimidine derivative 2 was allowed to react with different monosaccharides namely: D-arabinose, D-glucose and

D-mannose in absolute ethanol acidified with acetic acid to give the corresponding derivatives 5a-c. Mass spectra of

the latter derivatives represented the molecular ion peaks which were in agreement with their molecular formulae.

The derivative 3 was a versatile precursor for the synthesis of pyrazoline and isoxazole derivatives 6-8. Thus, upon its

condensation with hydrazine hydrate 98% and phenyl hydrazine in ethanol led to the formation of 2,3,3a,8-tetrahydro

and/or (2-phenyl-2,8-dihydro) pyrazolo [3',4':4,5] thiazolo [3,2-a]pyrimidine derivatives 6, 7, respectively. While,

heating of compound 3 with hydroxylamine hydrochloride in ethanolic sodium hydroxide solution furnished the

corresponding 8H-isoxazolo [3',4':4,5] thiazolo[3,2-a]pyrimidine analogue 8 (scheme 1). IR spectra of the novel

pyrazoline and isoxazole derivatives revealed the presence of an absorption band at 1703-1710 cm_1 due to the acetyl

C=O group and the disappearance of C=O band of the thiazolidine ring, instead a stretching absorption band appeared

at 3346 cm_1 referring to NH group in case of the pyrazoline derivative 6. 1H NMR spectra of compound 6,7 showed

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two doublets at the range δ γ.γ0-4.42 corresponding to the two methine protons of the pyrazoline ring besides the

other expected protons that were presented at their exact ranges. Mass spectra of the 6,7,8 exhibited their molecular

ion peaks that confirmed their molecular formulae.

The reaction of 1b with different chloro derivatives such as chloroacetic acid and bis(chloroethyl) ether in ethanolic

potassium hydroxide solution furnished the corresponding compounds 9, 10, respectively. While, condensation

reaction of the thioxo derivative 1b with a secondary nitrogen nucleophile such as piperidine yielded the

corresponding piperidin-1,6-dihydropyrimidine derivative 11. IR spectrum of the thioacetic acid 9 displayed four

absorption bands at 3426, 3230, 1730, 1710 cm_1 due to the presence of OH, NH and 2C=O groups, respectively. At

the same time, 1H NMR spectrum of 9 revealed a new singlet at δ γ.45 ppm contributed to the methylene protons of

the thioacetic acid side chain, besides the two singlet signals of the methyl and acetyl protons of the parent core. 13C

NMR spectrum of the same compound showed five characteristic signals at δ 18.5, ββ.7, γ1.5, 176.0, 1λ5.5 ppm due

to the carbons of CH3, COCH3, CH2 and 2C=O groups, in addition to the other expected signals that appeared at their

correct places. With regard to compound 10, its 1H NMR spectrum represented four triplets at δ β.71, γ.50, γ.60, γ.λ1

ppm that are referring to the 4CH2 of bis(chloroethyl) ether side chain, in addition to the other expected signals of the

molecule. IR spectrum of compound 11 showed absorption bands at 3226 and 1703 due to NH and C=O cm_1,

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respectively and the disappearance of C=S absorption band. Also, its 1H NMR spectrum exhibited, besides the

expected methyl and aromatic signals, two new multiplet signals at δ 1.55-1.65 ppm due to , CH2 and at δ γ.1β

contributing to α βCH2 groups of piperidine ring.

Hydrazinolysis of 1b was performed by its heating with excess hydrazine hydrate in ethyl alcohol to achieve the

hydrazinyl derivative 12, which was used as a precursor for condensation with different acid anhydride derivatives

such as phthalic anhydride and/or dichloromaleic anhydride in acetic acid to obtain isoindoline 1,3-dione and

dichloro-1H-pyrrole-2,5-dione derivatives 13a,b, respectively (scheme 2). IR spectra of the obtained compounds

13a,b displayed characteristic peaks at the regions 3220-3190 and 1737-1698 cm_1 contributing to NH, C=O groups,

respectively. Mass spectra of the compounds 12, 13a,b revealed their molecular ion peaks at m/z: 294, 424 and 443

respectively which confirm their molecular formulae.

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Since the chloropyrimidine moiety is a versatile precursor for the preparation of various nitrogen bridge heterocyclic

compounds, the 2-oxopyrimidine derivative 1a was heated with PCl5 /POCl3 for 5h on a water bath for its conversion

to 2-chloropyrimidine derivative 14. Nucleophilic displacement of chlorine atom was carried out by the treatment of

the chloro derivative 14 with different sulfa drugs namely: sulfapyridine and sulfadiazine to get the corresponding

sulfonamide derivatives 15a,b. IR spectra of 15a,b revealed different absorption bands at the ranges 3360-3330

(NH), 1706 (C=O) and 1396-1338, 1195-1176 (SO2). Mass spectra of the same compounds represented their

molecular ion peaks at m/z: 511 and 512, respectively. Moreover, the compound 1b was allowed to react with

paraformaldehyde and different secondary amines such as N,N-dimethylamine, morpholine and p-toluidine to obtain

the corresponding Mannich bases 16a-c (scheme 3). IR spectra of the mannich bases 16a,b revealed the

disappearance of NH bands of the parent molecules, while the absorption peaks of the acetyl C=O groups appeared at

their expected ranges. Also, 1H NMR spectra were in agreement with the proposed structures of the gained products.

In vitro antitumor Activity

Thirteen of the newly synthesized compounds were selected as representative examples to examine their in vitro

antitumor activities against human liver (HepG2) and colorectal (HCT-116) cancer cell lines using MTT assay. The

examined derivatives were 2, 3, 4, 5a-c, 8, 9, 10, 11, 16a-c. The percentage of the intact cells was measured and

compared to the control (Figure 2). The activities of the derivatives against the tested carcinoma cells were compared

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Manal M. Anwar* et al. International Journal Of Pharmacy & Technology
®
with that of Doxorubicin as a reference drug. The results showed that the most potent antitumor activity that is

equivalent to that of the reference drug was gained by the thiopyrimidine-acetic acid derivative 9 against both HepG2

and HCT-116 cancer cell lines (growth inhibition; 75, 70%, respectively). Meanwhile, the attachment of glucose

monosaccharide to the thiazolo[3,2-a]pyrimidine derivative 2 at C2 via ethylene linkage led to the formation of

compound 5b of potent cytotoxic activity against the tested carcinoma cell lines but slightly less than the potency of

doxorubicin (growth inhibition 60, 56%, respectively). Unfortunately, the rest of the evaluated derivatives showed

weak to moderate antitumor activity. Recent studies have indicated that exposure of tumor cells to an acidic medium

induces cell death through apoptosis of cells in G1 phase. Cell death caused by certain chemotherapy drugs was

attributable to an acidification of cells as a result of inhibition of intracellular pH regulation mechanisms caused by

H2O2 produced by mitochondria. Inhibition of pHi regulation will cause a reduction of pHi preferentially in tumor

cells in acidic extracellular environment relative to normal cells and thus cause damage preferentially in tumor cells

[53,54]. This knowledge might explain the significant antitumor effect of the acid derivative 9. Furthermore, probably

because of the progressively increasing intermittent or permanent hypoxia of tumor cells, they in response increase

the hyperglycolytic activity characterized by increased glucose uptake and formation of lactic acid [53,54]. Thus, the

marked activity of the derivative bearing thiazolo[3,2-a]pyrimidine tagged with glucose side chain 5b can be

explained by its uptake by the cancer cells where the glucose moiety is degraded leading to increase the acidity inside

the tumor cells, in addition to the expected cytotoxic effect of the parent thiazolo[3,2-a]pyrimidine core [55].

Figure (2). In vitro tumor growth inhibition activities of some of the newly synthesized compounds against (HepG-2)

and HCT-116 carcinoma cell lines at concentration of 100 M

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Manal M. Anwar* et al. International Journal Of Pharmacy & Technology
Furthermore, IC50 of compounds 5b and 9 were measured against both human liver (HepG2) and colorectal (HCT-

116) cancer cell lines. Table (2) showed IC50 of 88.9 and 85.4 µM corresponding to the compounds 5b and 9 against

HepG2 cancer cells. While, both compounds showed IC50 of 79.5 and 89.3µM against the colorectal cancer cell,

respectively.
Compound HepG-2 HCT-116

IC50

5b 88.9 79.5
9 85.4 89.3

Table (1). IC50 (µM) of compounds 5b, 9 against (HepG-2) and HCT-116 carcinoma cell lines.

In vitro Antioxidant Activity

Also, this study deals with the investigation of in vitro antioxidant activities against DPPH of the same thirteen

compounds, 2, 3, 4, 5a-c, 8, 9, 10, 11, 16a-c (Figure 3). The results obtained revealed that all of the tested

compounds showed dose dependent DPPH inhibition activities, which were reflected by their IC 50 values as

summarized in table (2). The activities of the compounds appeared in the following order: 16a > 3 > 10 > rutin > 4 >

5b > 5c > 2> 16b > 16c > 5a > 8 > 11 > 9 > vit C.

Comparing the activity of the thirteen compounds to the standard antioxidants and well known potent DPPH

inhibitors (rutin and vit C); It is obvious that all the newly synthesized compounds showed better or comparable

scavenging properties to that of rutin and vitamin C.

Figure (3). Antioxidant activity of the tested derivatives using DPPH.

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Manal M. Anwar* et al. International Journal Of Pharmacy & Technology
Table-2: The Antioxidant activities (IC50; µM) of the tested compounds.

Compound IC50

2 24.6

3 17.3

4 23.1

5a 30. 7

5b 24.3

5c 24.5

8 32.6

9 33.4

10 20.5

11 32.9

16a 13.9

16b 25.1

16c 27.9

Rutin 21.7

Vit C 39.3

Conclusion

This study reveals successful synthesis of new derivatives of pyrimidine either fused or conjugated with different

heteroaryl ring systems. Anticancer evaluation of some of the synthesized derivatives exhibited that compounds 9, 5b

appeared to be the most active cytotoxic compounds against human liver (HepG2) and colorectal (HCT-116) cancer

cell lines. They produced growth inhibition of the tested cancer cells equal to or slightly less than that of the standard

drug doxorubicin. It is noteworthy that the antioxidant examination of these derivatives exhibited that all of them are

potent antioxidants when comparing with rutin and vitamin C as reference drugs. Thus, further biological studies

could be carried out for these compounds as they can be considered as templates for antioxidant supplements.

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Manal M. Anwar* et al. International Journal Of Pharmacy & Technology
Acknowledgements

The authors are grateful to National Research Centre/ Cairo/ Egypt for providing infrastructures and other facilities

for carrying out this study.

Conflict of interests

The authors confirm that this article content has no conflict of interest.

References

1. Hussain MMM, Bhat KI, Revanasiddappab BC, Bharathi DR. Synthesis and Biological Evaluation of Some

Novel 2-Mercapto Pyrimidines. Int J Pharm Pharm Sci 2013; 5 (2): 471-473.

2. Mohamed MS, Awad SM, Zohny YM, Mohamed ZM. New Thiopyrimidine Derivatives of Expected Anti-

inflammatory Activity. Pharmacophore 2012; 3 (1): 62-75.

3. Nag S, Pathak R, Kumar M, Shukla PK, Batra S. Synthesis and antibacterial evaluation of ureides of Baylis–

Hillman derivatives. Bioorg & Med Chem. 2006; 16: 3824–3828.

4. Hoffmann HH, Kunz A, Simon VA, Palese P, Shaw ML. Broad-spectrum antiviral that interferes with de novo

pyrimidine biosynthesis. Proc Natl Acad Sci U S A 2011; 108 (14):5777–5782.

5. Clercq ED, Holý Somnath Naga, A. Acyclic nucleoside phosphonates: a key class of antiviral drugs. NAT REV

DRUG DISCOV 2005; 4:928-940.

6. Trivedi AR, Dodiya DK, Ravat NR, Shah VH. Synthesis and biological evaluation of some new pyrimidines via

a novel chalcone series. ARKIVOC 2008; (xi): 131-141.

7. Trivedi AR, Siddiqui AB, Shah VH. Design, synthesis, characterization and antitubercular activity of some 2-

heterocycle-substituted phenothiazines. ARKIVOC 2008; (ii): 210-217.

8. Agarwal A, Srivastava K, Puri SK, Chauhan PMS. Synthesis of 2,4,6-trisubstituted pyrimidines as antimalarial

agents. Bioorg Med Chem 2005; 13 (15), 4645–4650.

9. Agarwal A, Srivastava K, Puri SK, Sinha S, Chauhan PMS. A small library of trisubstituted pyrimidines as

antimalarial and antitubercular agents. Bioorg. Med. Chem. Lett. 2005; 15 (23): 5218–5221.

10. Sondhi SM, Dinodia M, Rani R, Shukla R, Raghubir R. Synthesis, anti-inflammatory and analgesic activity

evaluation of some pyrimidine derivatives. Indian J. Chem 2009; 49b: 273-281.

11. EL-gazzar ABA, Hussein HAR, Hafez HN. Synthesis and biological evaluation of thieno[2,3-d]pyrimidine

derivatives for anti-inflammatory, analgesic and ulcerogenic activity. Acta Pharm. 2007; 57:395–411.

IJPT| July-2015 | Vol. 7 | Issue No.1 | 8061-8085 Page 8081


Manal M. Anwar* et al. International Journal Of Pharmacy & Technology
12. Majeed J, Shaharyar M. Synthesis and in vivo diuretic activity of some novel pyrimidine derivatives. J. Enzyme

Inhib. Med. Chem 2011; 26 (6): 819-826.

13. Morris GW, Iams TA, Slepchenko KG, McKee EE. Origin of pyrimidine deoxyribonucleotide pools in perfused

rat heartμ implications for γ′-azido-γ′-deoxythymidine-dependent cardiotoxicity. Biochem. J. 2009; 422: 513–

520.

14. Reading SA, Earley S, Waldron BJ, Welsh DG, Brayden JE. TRPC3 mediates pyrimidine receptor-induced

depolarization of cerebral arteries. Am. J. Physiol. Heart Circ. Physiol 2005; 288 (5): H2055-H2061.

15. Jain KS, Chitre TS, Miniyar PB, Kathiravan MK, Bendre VS, Veer VS, Shahane SR, Shishoo .J. Biological and

medicinal significance of pyrimidines. Curr. Sci 2006; 90 (6):793-803.

16. Mishra R, Tomar I. Pyrimidine: The Molecule of Diverse Biological and Medicinal Importance. IJPSR 2011;

2(4):758-771.

17. Abu-Hashem AA, El-Shehry MF, Badria FA. Design and synthesis of novel thiophene- carbohydrazide,

thienopyrazole and thienopyrimidine derivatives as antioxidant and antitumor agents. Acta Pharm 2010; 60:

311–323.

18. Padmaja A, Payani T, Reddy GD. Synthesis, antimicrobial and antioxidant activities of substituted pyrazoles,

isoxazoles, pyrimidine and thioxopyrimidine derivatives. Eur J Med Chem 2009; 44 (11): 4557–4566.

19. Yan W, Ruan Z, Wang Y, Van Kirk K, Zhengping M, Brian JA. Discovery and Structure−Activity

Relationships of Trisubstituted Pyrimidines/Pyridines as Novel Calcium-Sensing Receptor Antagonists. J Med

Chem 2009; 52 (4): 1204–1208.

20. Gillespie RJ, Bamford S J, Botting R, Comer M, Denny S, Gaur S. Antagonists of the Human A 2A Adenosine

Receptor. 4. Design, Synthesis, and Preclinical Evaluation of 7-Aryltriazolo[4,5-d]pyrimidines, J Me. Chem

2009; 52 (1): 33–47.

21. Ahmed SA, Naji TS, Mohammad FI. Synthesis, Characterization and Cytotoxic Activity of Some Pyrimidine

Derivatives. J N U S 2013; 16 (2): 84-92.

22. Zhang J, Yang PL, Gray NS. Targeting cancer with small molecule kinase inhibitors. Nat. Rev. Cancer 2009; 9:

28–39.

IJPT| July-2015 | Vol. 7 | Issue No.1 | 8061-8085 Page 8082


Manal M. Anwar* et al. International Journal Of Pharmacy & Technology
23. Fathalla, O.A.M.; Ismail, M.A.H.; Anwar M.M.; Abouzid, K.A.M.; Ramadan, A. A.K. Novel 2-thiopyrimidine

derivatives as CDK2 inhibitors: molecular modeling, synthesis, and anti-tumor activity evaluation. Med Chem

Res. 2013; 22: 659–673.

24. Nasr T, Bondock S, Youns M. Anticancer activity of new coumarin substituted hydrazide-hydrazone derivatives.

Eur J Med Chem 2014; 76: 539-548.

25. Sashidhara V.K, Kumar A, Kumar M, Sarkar J, Sinha S. Synthesis and in vitro evaluation of novel coumarin–

chalcone hybrids as potential anticancer agents. Bioorg Med Chem Lett 2010; 20:7205–7211.

26. Hassan GS. Synthesis and antitumor activity of certain new thiazolo [2,3-b]quinazoline and thiazolo[3,2-

a]pyrimidine analogs Med Chem Res 2014; 23: 388-401.

27. De Oliveira, A.M.F.; Pinheiro, L.S.; Pereira, C.K.S; Matias, W.N.; Gomes, R.A.; Chaves, O.S. Total Phenolic

Content and Antioxidant Activity of Some Malvaceae Family Species. Antioxidants 2012; 1:33-43.

28. Abdalla MY. Glutathione as Potential Target for Cancer Therapy; More or Less is Good?. Jordan j. biol. sci.
2011; 4 (3):119 – 124.
29. Hamdy NA, Anwar MM, Abu-zied KM, Awad HM. Synthesis, Tumor Inhibitory, and Antioxidant Activity of
New Polyfunctionally 2-Substituted 5,6,7,8-Tetrahydronaphthalene Derivatives Containing Pyridine,
Thioxopyridine and Pyrazolopyridine Moieties. Acta Poloniae Pharmaceutica n Drug Research 2013; 70 (6),
987-1001.
30. Kotb ER, Anwar MA, Soliman MS, Salama MA. Synthesis and Reactions of Some Novel Quinoxalines for
Anticancer Evaluation. Phosphorus, Sulfur, and Silicon and the Related Elements 2007; 182:1119–1130.
31. Amin KM, Anwar MM, Syam YM, Khedr M, Kamel MM, Kassem EMM. A Novel Class of Substituted
Spiro[Quinazoline-2,1’-Cyclohexane] Derivatives as Effective PARP-1 Inhibitors: Molecular Modeling,
Synthesis, Cytotoxic and Enzyme Assay Evaluation. Acta Poloniae Pharmaceutica-Drug Research 2013; 70
(4):687-708.
32. Mohi El-Deen EM, Anwar MM, Kotb ER. Synthesis and Cytotoxic Evaluation of New 6,7,8,9-
Tetrahydropyrido[3',2':4,5]thieno[3,2-b] quinoline Derivatives. RJPBCS 2014; 5(6):1535-1549.
33. Amin KM, Anwar MM, Kamel M, Kassem EMM, Syam YM, EL-seginy SA. Synthesis, Cytotoxic Evaluation
and Molecular Docking Study of Novel Quinazoline Derivatives as PARP-1 Inhibitors. Acta Poloniae
Pharmaceutica-Drug Research 2013; 70 (5):833-849.
34. Ghorab MM, Bashandy MS, Alsaid MS. Novel thiophene derivatives with sulfonamide, isoxazole,
benzothiazole, quinoline and anthracene moieties as potential anticancer agents. Acta Pharm 2014; 64:419–431.
35. Youssef MM, Amin MA. Microwave Assisted Synthesis of Some New Thiazolopyrimidine,
Thiazolodipyrimidine and Thiazolopyrimidothiazolopyrimidine Derivatives with Potential Antioxidant and
Antimicrobial Activity. Molecules 2012; 17: 9652-9667.

IJPT| July-2015 | Vol. 7 | Issue No.1 | 8061-8085 Page 8083


Manal M. Anwar* et al. International Journal Of Pharmacy & Technology
36. Ghorab MM, El-Gazzar MG, Alsaid MS. Synthesis, Characterization and Anti-Breast Cancer Activity of New 4-
Aminoantipyrine-Based Heterocycles. Int J Mol Sci 2014; 15: 7539-7553.
37. Nofal ZM, Soliman EA, Abd El-Karim SS, El-Zahar MI, Srour AM, Sethumadhavan S, Maher TJ. Synthesis of
Some New Benzimidazole–Thiazole Derivatives as Anticancer Agents. J. Heterocyclic Chem 2014, 51:1797.
38. Sabastiyan A, Suvaikin MY. Synthesis, characterization and antimicrobial activity of 2-
(dimethylaminomethyl)isoindoline-1,3-dione and its cobalt(II) and nickel(II) complexes. Adv App. Sci Res 2012;
3 (1):45-50.
39. Jin YZ, Fu DX, Ma N, Li ZC, Liu QH, Xiao L, Zhang RH. Synthesis and Biological Evaluation of 3-Substituted-
indolin-2-one Derivatives Containing Chloropyrrole Moieties. Molecules 2011; 16: 9368-9385.
40. Bala S, Sharma N, Kajal A, Kamboj S, Saini V. Mannich Bases: An Important Pharmacophore in Present
Scenario. Int J Med Chem 2014; 2014:1-15.
41. Awad HM, Abd-Alla HI, Mahmoud KH, El-Toumy SA. In vitro anti-nitrosative, antioxidant, and cytotoxicity
activities of plant flavonoids: a comparative study. Med Chem Res 2014; 23 (7):3298-3307.
42. Almajhdi FN, Fouad H, Khali KA, Awad HM, Mohamed SHS.; Elsarnagawy T, Albarrag AM, Al-Jassi, FF,
Abdo HS. In-vitro anticancer and antimicrobial activities of PLGA/silver nanofibers composites prepared by
electrospinning. J Mater Sci Mater Med 2014; 25:1–9.
43. Michael HN, Awad HM, El-Sayed NH, Pare PW. Chemical and antioxidant investigations: Norfolk pine needles
(Araucaria excelsa). Pharm Biol 2010; 48 (5):534-538.
44. Soliman, H.A.; Yousif, M.N.M.; Said, M.M.; Hassan, N.A.; Ali, M.M.; Awad, H.M.; Abdel-
Megeid, F.M.E. Synthesis of novel 1,6-naphthyridines, pyrano[3,2-c]pyridines and pyrido[4,3-d]pyrimidines
derived from 2,2,6,6-tetramethylpiperidin-4-one for in vitro anticancer and antioxidant evaluation. Der Pharma
Chemica, 2014; 6(3):394-410.
45. Narsaiah AV, Basak AK, Nagaiah K. Cadmium chloride: an efficient catalyst for one-pot synthesis of 3,4-
dihydropyrimidine-2(1H)-ones. Synthesis 2004; 8:1253-1256.
46. Srinivas KVNS. Iodine catalyzed one-pot synthesis of 3, 4-dihydropyrimidine-2(1H)-ones and thiones: a simple
and efficient procedure for the Biginelli reaction. Synthesis 2004; 13:2091-2093.
47. De SK, Gibbs RA. Ruthenium (III) chloride-catalyzed one-pot synthesis of 3,4-dihydropyrimidin-2-(1H)-ones
under solvent-free conditions. Synthesis 2005; 11:1748-1750.
48. Peng, J.; Deng, Y. Ionic liquids catalyzed Biginelli reaction under solvent-free conditions. Tetrahedron Lett
2001; 42:5917-5919.
49. Solanki MJ, Chavda MM. Synthesis and Antimicrobial Activity of Some Novel Derivatives of Thiazolo[2,3-
b]dihydropyrimidine Containing 4-Pyrazole Moiety. Rasayan J Chem 2011; 4 (3):605-608.
50. Yossef MM, Mohamed SF, Kotb ER, Salama MA. A novel Synthesis of Some New Pyrimidine,
Thiazolopyrimidine and Pyrazole Derivatives Using Diarylepoxypropanones as Precursors. World J Chem 2009;
4(2):149-156.
51. Vicini P, Geronikaki A, Anastasia K, Incerti M, Zani F. Synthesis and antimicrobial activity of novel 2-
thiazolylimino-5-arylidene-thiazolidinones. Bioorg Med Chem 2006; 14:3859-3864.

IJPT| July-2015 | Vol. 7 | Issue No.1 | 8061-8085 Page 8084


Manal M. Anwar* et al. International Journal Of Pharmacy & Technology
52. Ottana R, Maccari R, Barreca ML, Bruno G, Rotondo A, Rossi A, Chiricosta G, Di-Paola R., Sautebin L,
Cuzzocrea S, Vigorita MG. 5-Arylidene-2-imino-4-thiazolidinones: Design and synthesis of novel anti-
inflammatory agents. Bioorg Med Chem 2005; 13: 4243-4252.
53. Hirpara JL, Clements MV, Pervaiz A. Intracellular acidification triggered by mitochondrial-derived hydrogen
peroxide is an effector mechanism for drug-induced apoptosis in tumor cells. J Biol Chem 2001; 276: 514–521.
54. Ahmad KS, Iskandar KB, Hirpara JL, Clement MV, Pervaiz S. Hydrogen peroxide-mediated cytosolic
acidification is a signal for mitochondrial translocation of Bax during drug-induced apoptosis of tumor cells.
Cancer Res 2004; 64:7867–7878.
55. Abdo NYM. Synthesis and Antitumor Evaluation of Novel Dihydropyrimidine, Thiazolo[3,2-a]pyrimidine and
Pyrano[2,3-d]pyrimidine Derivatives. Acta Chim. Slov 2015; 62:1-13.

* Corresponding author:
Manal M. Anwar*,
Therapeutical Chemistry Department, National Research Center, Dokki, Giza, Cairo, Egypt.
Tel: 0123956970; Fax: + (202) 337-0931
E-mail: manal.hasan52@live.com
E-mail: Manal.hassan232@ymail.com

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