New thiazolopyrimidine as anticancer agents: Synthesis, biological evaluation, DNA binding, molecular modeling and ADMET study

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New Thiazolopyrimidine as anticancer agents: Synthesis, biological evalua‐

tion, DNA binding, Molecular modeling and ADMET study

Sara T. Al-Rashood, Shymaa S. Elshahawy, Asmaa M. El-Qaias, Dina S. El-

Behedy, Alshaimaa A. Hassanin, Selwan M. El-Sayed, Shahenda M. El-

Messery, Moataz A. Shaldam, Ghada S. Hassan

PII:

S0960-894X(20)30722-8

DOI:

Reference:

https://doi.org/10.1016/j.bmcl.2020.127611

BMCL 127611

To appear in:

Bioorganic & Medicinal Chemistry Letters

Received Date:

Revised Date:

Accepted Date:

22 June 2020

4 October 2020

8 October 2020

Please cite this article as: Al-Rashood, S.T., Elshahawy, S.S., El-Qaias, A.M., El-Behedy, D.S., Hassanin, A.A.,

El-Sayed, S.M., El-Messery, S.M., Shaldam, M.A., Hassan, G.S., New Thiazolopyrimidine as anticancer agents:

Synthesis, biological evaluation, DNA binding, Molecular modeling and ADMET study, Bioorganic & Medicinal

Chemistry Letters (2020), doi: https://doi.org/10.1016/j.bmcl.2020.127611

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New Thiazolopyrimidine as anticancer agents: Synthesis, biological

evaluation, DNA binding, Molecular modeling and ADMET study.

Sara T. Al-Rashood^a, Shymaa S. Elshahawy^b, Asmaa M. El-Qaias^b, Dina S. El-Behedy ^b, Alshaimaa A.

Hassanin^b, Selwan M. El-Sayed^c, Shahenda M. El-Messery^d*, Moataz A. Shaldam^e, Ghada S. Hassan^c

^aDepartment of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia.

^bFaculty of Pharmacy, Mansoura University, P.O.Box 35516, Mansoura, Egypt

^cDepartment of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, P.O.Box 35516, Mansoura, Egypt

^*Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, P.O.Box 35516, Mansoura, Egypt

d

^eDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafr El Sheikh, 33516, Egypt

*Corresponding author. Department of Pharmaceutical Organic Chem., Faculty of Pharmacy, Mansoura

University, P.O.Box 35516, Mansoura, Egypt. E-mail: selmessery@gmail.com. Tel, Fax: +20-50-2200242

Abstract

In the present study, new series of thiazolopyrimidine derivatives was synthesized as purine analogs.

The structures of the products were confirmed through spectroscopic techniques such as NMR and

mass spectrometry. In addition, the synthesized compounds were evaluated as antitumor active agent

through NCI screening protocol against 60 different cell lines under 9 different panels. Furthermore,

DNA binding activity of the compounds was also evaluated. The results revealed that compound 35

proved to be the most active member of the tested series and it is promoted to the 5-dose testing where

it gives GI₅₀, TGI and LC₅₀values of 1.07, 6.61, 34.7 M respectively. Furthermore, it also proved to

have a good DNA binding activity with value that is comparable with that produced by doxorubicin

which was used as positive standard. In addition, compound 27 was proved to be the most active

DNA binding agent with binding affinity 28.38 ± 1.1. The pharmacokinetic properties were also

calculated. Molecular docking studies suggested binding mode of compounds 27 and 35 to DNA

minor groove via hydrogen bonding interaction. The anticancer activity of compounds 27 and 35 may

be attributed to DNA binding.

Keywords: Synthesis, thiazolopyrimidine, purine, DNA-binding, antitumor, ADMET, Molecular

Docking

Nitrogenous bases are heterocyclic scaffolds that play several important roles in biology. They are the

major skeleton of many vital biomolecules. Both pyrimidine and purine pharmacophores are the

building blocks that form the backbone of genetic information carrying molecules such as DNA and

RNA. Also, they are involved in other biological processes such as cell signaling. This caused a

considerable utilization of them in the drug designing process of several chemotherapeutic agents,

cardiovascular as well as agrochemical and veterinary drugs [1]. Many purine and pyrimidine analogs

have versatile biological activity including anti-inflammatory and analgesic, antimicrobial, anti-avian

influenza virus (H5N1), against herpes simplex virus type-1 (HSV-1) and hepatitis-A virus (HAV),

serotonin 5-HT₆receptor antagonist, anti-arrhythmic agents, etc. [2,3].

1

The pyrimidine core constructs the major skeleton of many well-known medications such as

fluorouracil, etravirine, risperidone, iclaprim, avanafil and rosuvastatin. On the other hand, many

drugs are modified purines such as cladribine, tioguanine, clofarabine, mercaptopurine, fludarabine

and nelarabine. These represent a broad number of medication classes resulting in drawing the

attention to such class of compounds as candidates for design and development of new biologically

active compounds [4-11].

Taking a closer look to the anticancer activity of both purine and pyrimidine analogs, these skeletons

are involved in many antimetabolites that were used for decades as chemotherapeutic drugs, for

example, 6-mecaptopurine (Lukerine), thioguanine, azathioprine (Imuran) and azaguanine

(Guanazole) represents examples of purine bases-containing drugs while 5-fluorouracil (Fluroplex),

cytarabine (Cytosar) represents the most known pyrimidine containing chemotherapeutic agents [12].

These drugs mainly act through the inhibition of many enzymes involved in both salvage and de novo

synthesis of purine and pyrimidine bases such as phosphoribosyl transferase, aminotransferase, adenyl

succinate synthase, adenyl succinate lyase and etc….. [12]. In many cases, the purine metabolites can

block certain enzymatic pathways or they can mimic the reactivity of the natural purines as substrates

to be metabolized to their corresponding ribonucleotide and deoxyribonucleotide triphosphates and

subsequently incorporated into DNA and RNA. As a result, interference with nucleic acid synthesis

and function causes multiple types of toxicities [5,6].

Thiazolopyrimidines are purine isosteres which are involved in many drug skeletons, (Fig. 1 A) it was

revealed that thiazolo[3,2-a]pyrimidine (Fig. 1 B) is an efficient scaffold in the field of anticancer

research as well as chemotherapeutic agents. Their activity was proved to be attributed to the

intercalation with the DNA that is the major target in fighting the cancer cells [13,14]. Most of the

well-known agents which are successfully used in clinical treatment are small molecules that are able

to interact with nucleic acid mostly through one of these modes: intercalation, groove binding or

electrostatic interactions [15, 16]. In view of the mentioned data and in continuation of our work [17-

20], we synthesized new thiazolo[3,2-a]pyrimidine analogs in a trial to discover more selective and

potent antitumor agents (Fig.2). through the designing process of the target compounds many features

that revealed to be important in the synthesized structure were preserved. These results were obtained

from the previous work already published. From these features, the methoxy groups that are known

to enhance the antitumor potency [21, 22]. The second feature is represented by the ethyl carboxylate

moiety that improve the activity of compounds containing it [17]. In-vitro anticancer screening of the

synthesized compounds was conducted by the NCI protocol on 60 cell lines cancer subpanels namely

[23-25]. In addition, DNA binding assay of the synthesized compounds was also conducted as a trial

2

for detection of the mechanism of action of the most potent compounds of the synthesized series [26].

In silico study describing the properties of the target compounds and DNA binding activities were

also carried out. The structures of the synthesized compounds were confirmed by different

spectroscopic techniques involving H¹NMR, C¹³NMR and mass spectroscopy. In addition, the

products were evaluated as antitumor agent through NCI screening protocol against 60 different cell

lines under 9 different panels: Leukemia, Renal cancer, CNS cancer, Prostate cancer, Non-small lung

cancer, Colon cancer, Ovarian cancer, Breast cancer and Melanoma. Furthermore, DNA binding

activity of the compounds was also evaluated.

Figure 1 Structures of important reference anticancer agents

Figure 2 Structures of the designed synthesized compounds

The synthetic strategy for the synthesis of the target products 15-29, 31-35 and 38-41 is illustrated in

schemes 1 and 2. The intermediate compounds 7-11 were prepared through the interaction of pure

acetone and substituted benzaldehyde in 10 % alcoholic NaOH to yield the diarylidene derivatives

[18-20]. The latter were further reacted with either 2-aminothiazole (12), 2-amino-4-methylthiazole

(13), Ethyl 2-aminothiazole-4-carboxylate (14), 2-amino-5-methylthiazole (30) to afford the target

compounds 15-29 and 31-35.

3

The same strategy was adopted for the synthesis of compounds 38-41, as the substituted

benzaldehydes were replaced by 2-thiophene carboxaldehyde to yield the intermediate 37 which is

further reacted with substituted thiazoles 12-14 and 30 to give the target compounds 38-41 (Table 1).

The spectral data confirmed the structures of the target compounds. For example, the appearance of

the methyl and the ethyl ester group or even the appearance of additional aromatic protons of the

thiazole moiety in the HNMR spectrum indicates the formation of the products in addition to the

molecular weight in the mass spectrometric charts.

Scheme 1: Synthesis of compounds 15-29 and 31-35

Scheme 2: Synthesis of compounds 38-41

4

Table 1: Physicochemical Properties of the target compounds 15-29, 31-35 and 38-41

Comp.

no

15

16

17

18

19

20

21

22

23

24

25

Yield Comp.

Yield

%

59

66

61

55

52

54

49

42

55

49

44

42

R

R¹

R²

R³

m.p.

R

R¹

H

R²

R³

m.p.

%

55

58

61

55

62

43

59

61

46

52

76

65

no

27

28

29

31

32

33

34

35

38

39

40

41

H

Cl

CH₃

OCH₃

H

140-3

153-6

166-9

175-7

204-9

151-4

180-3

137-9

126-9

194-8

171-5

130-4

COOC₂H₅

COOC₂H₅OCH₃OCH₃

COOC₂H₅OCH₃OCH₃OCH₃

OCH₃

H

188-90

200-3

176-80

144-5

121-5

157-62

134-7

191-5

190-3

215-7

164-8

220-4

OCH₃OCH₃

OCH₃OCH₃OCH₃

H

OCH₃OCH₃

OCH₃OCH₃OCH₃

H

-

H

Cl

CH₃

OCH₃

H

CH₃

COOC₂H₅

Cl

CH₃

OCH₃

H

OCH₃OCH₃

OCH₃OCH₃OCH₃

-

H

CH₃

COOC₂H₅

-

Cl

CH₃

H

26

Fifteen of the synthesized compounds were screened using the NCI’s disease-oriented human cell

lines screening assay for their in-vitro antitumor activity using single dose (10 µM) of the test

compounds against 60 cell lines representing nine tumor subpanels namely; leukemia, non-small cell

lung, colon, CNS, melanoma, ovarian, renal, prostate, and breast cancer cells [23-25]. Compounds

that proved to be highly active were promoted to the five-dose screen. The data obtained were

presented in form of percentage growth inhibition (GI %). The obtained results of the tested thiazolo

[3,2-a]pyrimidine analogs showed distinctive potential pattern of selectivity, as well as broad-

spectrum antitumor activity (Tables 2 and 3). Doxorubicin was used as a positive control. As shown

in tables 2 and 3, it was observed that most of the synthesized compounds proved to be inactive against

almost all the tested cell lines, having GI% not exceeding 20% for most of the tested compounds. On

the other hand, compounds 29 and 35 proved to be the active members between the synthesized

products. Compound 29 showed activity against most of the tested cell lines with GI% ranging from

12.0- 69.3 %, in addition its activity was observed more against the Leukemia cell lines in which it

exerts its high GI% 69.3 value. Furthermore, concerning the most active compound 35, it showed

lethal effect on almost all the cell lines and its least GI% was achieved against CNS cancer (SNB-75),

these results promoted this compound to the 5-dose screening in which 5 different concentrations of

the compound under investigation are prepared and tested against the 9 different types of cancer cells.

5

It was observed that the GI₅₀of compound 35 was about 10 folds more than that of the reference

compound doxorubicin, and about the TGI is 3 folds more than the reference drug while the LC₅₀is

nearly equal to that of doxorubicin. By taking a closer look to each cell line individually, in general,

most of the target compounds showed inactivity against the majority of the cell lines used for

screening, but for example, leukemia cell lines, compounds 25, 29, 32 and 35 showed activity against

K-562 and MOLT-4. The Non-small cell lung cancer HOP-92 and NCI-H522 were also found to be

sensitive to some of the tested compounds such as 28, 29 and 35. Regarding CNS cancer cell line

SNB-75, it was observed that it is sensitive to a number of compounds with GI% inhibition ranging

from 12.3-75.6 %. Finally, renal cancer cell lines were also sensitive to some of the test compounds

18, 23, 25, 28, 29, 32 and 35.

Table 2: Percentage growth inhibition (GI%) of in vitro subpanel tumor cell lines at 10 M

concentration of the selected compounds

% Growth Inhibition (GI %)^a

Subpanel tumor cell

lines

Leukemia

17

18

23

24

25

28

29

31

32

35

38

39

Doxorubicin

CCRF-CEM

HL-60(TB)

K-562

MOLT-4

RPMI-8226

SR

-

69.3

-

35.7

25.1

18.0

59.0

-

L

97.8

L

-

L

97.9

L

-

12.4

16.7

-

12.6

-

13.8

-

Non-small cell lung cancer

A549/ATCC

HOP-62

HOP-92

NCI-H226

NCI-H23

NCI-322M

NCI-H460

NCI-H522

-

L

97.3

L

86.4

L

-

L

93.1

L

10.1

18.0

39.5

-

L

66.7

86.1

99.4

L

14.5

12.0

47.8

10.9

L

13.3

Colon cancer

COLO 205

HCC-2998

HCT-116

HCT-15

HT29

-

L

-

L

44.4

35.0

13.0

22.7

13.4

97.2

84.8

95.3

95.8

98.1

KM12

SW-620

CNS cancer

SF-268

SF-295

SF-539

SNB-19

SNB-75

U251

-

L

66.5

75.6

L

-

L

-

12.5

-

25.3

-

18.4

-

17.3

-

13.7

-

12.3

-

14.6

90.8

Melanoma

LOX IMVI

MALME-3M

M14

MDA-MB-435

SK-MEL-2

SK-MEL-28

SK-MEL-5

UACC-257

UACC-62

-

29.7

-

L

-

94.3

L

96.5

L

-

11.9

-

12.8

-

12.0

17.2

18.0

-

6

Ovarian cancer

IGORV1

-

L

88.4

L

91.9

80.6

L

-

L

85.9

L

95.1

86.2

OVCAR-4

OVCAR-5

OVCAR-8

NCI/ADR-RES

SK-OV-3

12.5

-

32.0

-

Renal cancer

786-0

A498

-

L

-

95.5

L

88.0

74.6

96.0

25.6

-

17.6

-

11.8

12.3

ACHN

CAKI-1

RXF 393

SN12C

TK-10

UO-31

-

12.8

-

11.3

11.7

20.2

13.7

19.1

Prostate cancer

PC-3

DU-145

17.2

-

11.3

-

21.1

-

L

-

98.7

86.8

-

Breast cancer

MCF7

MDA-MB-231/ATCC

HS 578T

BT-549

T-47D

-

28.9

14.5

-

L

98.0

L

92.0

L

-

96.6

96.2

L

MDA-MB-468

11.3

L

^a-, GI ˂ 10%; nt, not tested; L, compound proved lethal to the cancer cell line.

Table 3: Compound 35 Median growth inhibitory (GI₅₀, M), Total growth inhibitory (TGI, M)

and Median lethal (LC₅₀, M) concentrations of in vitro subpanel tumor cell lines

Compound Activity

I

II

III

IV

V

VI

VII

VIII

IX

MG-MID^a

GI₅₀0.43

TGI 61.93 4.81 3.62 10.15 3.37

1.94 0.92 1.85

0.99

1.75

33.9

1.49

4.38

1.69

1.39

1.07

6.61

34.7

35

52.9 17.90

68.71

LC₅₀

b

62.85 36.0 54.25 18.23 76.45 54.73

b

GI₅₀

TGI

LC₅₀

0.15

2.48

30.5

Doxorubicin

I, leukemia; II, non-small cell lung cancer; III, colon cancer; IV, CNS cancer; V, melanoma; VI, ovarian cancer; VII,

a

renal cancer; VIII, prostate cancer; IX, breast cancer. Full panel mean-graph midpoint (M). b Compounds showed

values > 100 M. nt, not tested.

DNA represents an important target for many drugs currently in clinical use or in advanced clinical

trials. It was proved that small molecules can act as potent antimicrobials via DNA intercalation.

Methyl green was used in Methyl green-DNA Displacement assay to reversibly bind to DNA, and the

colored complex is stable at neutral pH, whereas free methyl green fades at this pH value. Incubation

for 24 h, in the buffer used for displacement reactions in this study, results in virtually a complete loss

of methyl green absorbance. A colorimetric assay was used to measure the displacement of methyl

green from DNA by compounds with ability to bind to DNA [26]. From the obtained results, it was

observed that compound 27 is the most active one among the synthesized compounds; it had IC₅₀

value less than that obtained by the reference drug Doxorubicin. Other compounds proved to be active

7

such as compounds 28, 18, 26 and 38 with IC₅₀values of 29.86 ± 1.3, 30.05 ± 1.6, 31.49 ± 1.8 and

33.67 ± 1.8 respectively. On the other hand, compound 35 that represents the most active product in

the antitumor activity had IC₅₀value 36.13 ± 1.9 which is very close to the standard, giving indication

that its mechanism of action can be due to its DNA binding action (Table 4).

Table 4: DNA/methyl green colorimetric assay of the DNA-binding compounds

DNA-active

compound

DNA/methyl green (IC50

µg/ml)

DNA-active

compound

DNA/methyl green (IC50

µg/ml)

No.

*

1

2

3

4

5

6

7

8

DOX

15

16

17

18

19

20

21

22

23

24

25

26

31.27±1.8

56.33 ± 2.9

62.74 ± 3.2

47.75 ± 2.6

30.05 ± 1.6

55.42 ± 3.6

50.91 ± 2.7

83.41 ± 4.1

42.50 ± 2.1

72.54 ± 3.5

91.48 ± 4.6

79.28 ± 3.9

31.49 ± 1.8

13

14

15

16

17

18

19

20

21

22

23

24

27

28

29

31

32

33

34

35

38

39

40

41

28.38 ± 1.1

29.86 ± 1.3

43.92 ± 2.3

45.18 ± 2.5

87.57 ± 4.3

41.37 ± 2.1

58.32 ± 3.0

36.13 ± 1.9

33.67 ± 1.8

39.82 ± 2.0

66.01 ± 3.4

76.15 ± 3.7

9

10

11

12

The pharmacokinetic properties of the most active compounds 27 and 35 were calculated theoretically

by the use of online application PreADM E https://preadmet.bmdrc.kr. As shown in table 5, the tested

compounds showed excellent human intestinal absorption that can reach 100 %. Furthermore, they

have good plasma protein binding activity that exceeds 89.50 %, this data requires attention during

the use of other drugs as it can displace them leading to increase the potency of the concurrent

administered agents. It was also observed that the tested compounds have potency to penetrate the

BBB more than doxorubicin. The results revealed that the tested compounds have better oral

absorptivity and intestinal bioavailability than the standard drug used.

Oral bioavailability is considered an important factor for bioactive molecules development as

therapeutic agents [27]. Lipinski used some molecular descriptors in formulating “Rule of Five” to

assess the potential oral bioavailability and drug-likeness criteria of the molecules. Number of

hydrogen bond donor, hydrogen bond acceptor sites, molecular weight, logP values [28, 29]. In

addition, the total polar surface area (TPSA) and number of rotatable bonds (NROTB) represents

additional key properties for drug bioavailability. The obtained results for compounds 27 and 35

revealed that compound 27 has no violations whereas compound 35 has one violation concerning

Lipinski's rule. Number of rotatable bonds of compounds was <10, giving a hint about acceptable

molecular flexibility with expected improved permeability and oral bioavailability. TPSA value was

8

<140 Å²which indicates a good predicted oral bioavailability. From these data, it could be suggested

that both compounds can be used as good orally absorbed anticancer agent. All descriptors were

calculated by the DruLito software and the results are listed in Table 6 [30].

Table 5: ADMET profile for compounds 27 and 35

Comp.

HIA

PPB

BBB MDCK CaCo-2

CYP

AMES

Toxicity

Mutagen

Carcinogenecity

Inhibition

Inhibitor

Mouse

Rat

97.77

98.18

94.00

89.53

1.13

0.89

0.0776

0.0459

4.264

56.5653

29.3344

17.7512

Positive

Negative

Positive

Negative

27

35

Dox.

Mutagen

Non-Mutagen

37.28 40.53 0.03

Inhibitor

HIA : Human Intestinal Absorption, PPB: Plasma Protein Binding, BBB: Blood Brain Barrier, MDCK: Maden Darby Canine Kidney, CaCo-2: Predict intestinal

permeability and oral absorption of compounds

Table 6. Calculated Lipinski's rule of five and other in silico parameters for compounds 27 and 35

b

^aMolecular weight. Number of hydrogen bond acceptors. ^cNumber of hydrogen bond donors. ^dlogarithm of compound partition

e

f

coefficient between n-octanol and water. Number of violations of Lipinski rule. No. of rotatable bonds. ^gTopological polar surface

area (Å²).

In the present work, molecular modeling studies have been added as an important tool to understand

the DNA binding data obtained experimentally for the most active compounds 27 and 35 (concerning

DNA binding and in vitro antitumor screening, respectively) and rationalize their anticancer activity.

Conformational analysis of the target compounds 27 and 35 has been obtained by use of the MM

force-field as implemented in MOE, 2014. [31]. The lowest energy conformer of the selected active

compounds was represented in Figure 3. X-ray crystallographic structure of the DNA dodecamer

d(CGCAAATTTGCG) with its complex distamycin A was extracted from the Protein Data Bank

(PDB code: 2DND, Deposited: 1988-08-29 Released: 1989-01-09) for the docking study [32].

Distamycin reference had produced with DNA bases Adenine, Cytosine and through hydrogen

bonding network interactions with a calculated binding energy of -10.5674 kcal/A˚ mol (Figure 4a,b,

Comp.

27

Mwt^a

448.15

510.18

HBA^b

6

8

HBD^c

0

LogP^d

3.786

4.014

Lip. V^e

0

1

NROTB^f

8

9

TPSA^g

85.66

96.28

35

2D and 3D view). Compounds 27 and 35 were docked into DNA minor groove, they showed hydrogen

bonding interactions with binding energy of -10.2698 and -10.4532 kcal/A˚ mol, respectively (Figures

5a, b and 6a, b). Surface mapping study was performed for further investigation of activity pattern for

compounds 27 and 35. It showed a preference for more hydrophobic and H-bonding regions as more

green and pink areas on the surface maps can be found. This provides additional explanation for their

DNA binding activity. (Figure 7).

9

(b)

(a)

Figure 3: Lowest energy conformers of (a) compound 27 and (b) compound 35 with balls and

cylinders

(b)

(a)

Figure 4: (a) 2D and (b) 3D binding mode and residues involved in the recognition of reference

ligand Distamicin into DNA

(b)

Figure 5: (a) 2D binding mode and residues involved in the recognition of compound 35 into

DNA. (b) Overlay of compound 35 (pink) and Distamycin (green) into DNA minor

groove.

10

(b)

(a)

Figure 6: (a) 2D binding mode and residues involved in the recognition of compound 27 into

DNA. (b) Overlay of compound 27 (pink) and Distamycin (green) into DNA minor

groove.

(b)

(a)

Figure 7: Surface maps for (a) compound 27 and (a) compound 35 (hydrophobic: green, H-

bonding: pink, mild polar: blue)

A new series of thiazolopyrimidine derivatives were synthesized, their structures were confirmed by

different spectroscopic techniques. Antitumor screening data revealed that compound 35 exhibited

the highest activity among the entire synthesized products, it gives GI₅₀, TGI and LC₅₀values of 1.07,

6.61, 34.7 M respectively. Also, it was proved to be an active compound as DNA binding agent with

binding affinity 36.13 ± 1.9 with value that is comparable with that produced by doxorubicin which

was used as positive standard. Furthermore, compound 27 was proved to be the most active DNA

binding agent with binding affinity 28.38 ± 1.1. The ADMET study of the synthesized compounds

was also evaluated. Modeling study provides type of binding mode of compounds 27 and 35 into DNA

minor groove via hydrogen bonding. The anticancer mechanism of action of these compounds could

be attributed to DNA intercalation.

This manuscript submitted has not been previously published, nor is it before another journal for

consideration"

11

2. ACKNOWLEDGMENTS

The authors would like to extend their sincere appreciation to Researchers Supporting Project number

(RSP-2019/103), King Saud University, Riyadh, Saudi Arabia, for its funding this research.

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Highlights

 New series of thiazolopyrimidine derivatives has been synthesized.

 Antitumor screening according to NCI protocol against 60 different cell lines has been

performed

 DNA binding affinity of the synthesized compounds has been calculated.

 Predicted ADMET data for the target compounds were also estimated.

 Molecular modeling study has been conducted.

15

Graphical Abstract

New Thiazolopyrimidine as anticancer agents:

Synthesis, biological evaluation, DNA binding and

ADMET study.

Sara T. Al-Rashood, Shymaa S. Elshahawy, Asmaa M. El-Qaias, Dina

S. El-Behedy , Alshaimaa A. Hassanin, Selwan M. El-Sayed, Shahenda

M. El-Messery*, Moataz A. Shaldam, Ghada S. Hassan

16

Article Doi

New thiazolopyrimidine as anticancer agents: Synthesis, biological evaluation, DNA binding, molecular modeling and ADMET study

DOI: 10.1016/j.bmcl.2020.127611

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Article abstract of DOI:10.1016/j.bmcl.2020.127611

Full text of DOI:10.1016/j.bmcl.2020.127611

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