Design and synthesis of novel 5-aminosalicylate (5-ASA)–4-thiazolinone hybrid derivatives with promising antiproliferative activity

Article abstract of DOI:10.1016/j.bmcl.2016.02.073

Two privileged pharmacophores were assembled in one molecular frame involving 5-aminosalicylate and 4-thiazolinones that can be found in different stereochemical features. The compounds were fully characterized and evaluated for antiproliferative activity

Full text of DOI:10.1016/j.bmcl.2016.02.073

Accepted Manuscript
Design and synthesis of novel 5-aminosalicylates (5-ASA)- 4-thiazolinone hy-
brid derivatives with promising antiproliferative activity
Hajjaj H.M. Abdu-Allah, Samia G. Abdel-Moty, Raafat El-Awady, Abdel-
Nasser A. El-Shorbagi
PII:
S0960-894X(16)30198-6
DOI:
http://dx.doi.org/10.1016/j.bmcl.2016.02.073
BMCL 23627
Reference:
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
13 January 2016
23 February 2016
24 February 2016
Please cite this article as: Abdu-Allah, H.H.M., Abdel-Moty, S.G., El-Awady, R., El-Shorbagi, A.A., Design and
synthesis of novel 5-aminosalicylates (5-ASA)- 4-thiazolinone hybrid derivatives with promising antiproliferative
activity, Bioorganic & Medicinal Chemistry Letters (2016), doi: http://dx.doi.org/10.1016/j.bmcl.2016.02.073
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Design and synthesis of novel 5-aminosalicylates (5-ASA)- 4-thiazolinone hybrid derivatives
with promising antiproliferative activity
a *
a
b,c
Hajjaj H. M. Abdu-Allah , Samia G. Abdel-Moty , Raafat El-Awady , Abdel-Nasser A. El-
a,c
Shorbagi
a
Department Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Assiut University,
Assiut 71526, Egypt. E-mail: hagag.abdallah@pharm.au.edu.eg
b
Cancer Biology Department, National Cancer Institute, Cairo University,Cairo, Egypt
c
Sharjah Institute for Medical Research and College of Pharmacy, University of Sharjah,
Sharjah 27272, UAE
Keywords: 5-aminosalicylic, 4-thiazolinone, 4-thiazolidinone, stereochemistry, hybrid,
antiproliferative
*
Coressponding author
Department of pharmaceutical Organic Chemistry, Faculty of Pharmacy, Assiut University,
Assiut 71526, Egypt. Tel: 20-01010211566, 20-088-241594 & Fax: 002-088-2332776
E-mail: hagag.abdallah@pharm.au.edu.eg
1

Abstract
Two privileged pharmacophores were assembled in one molecular frame involving 5-
aminosalicylate and 4-thiazolinones that can be found in different stereochemical features. The
compounds were fully characterized and evaluated for antiproliferative activity against four
human cancer cell lines and some are equipotent to doxorubicin with lower cytotoxicity to
normal cells. The most interesting finding relates to compound 10, which shows an IC50 value of
7
0 nM against MCF-7 cells, while the IC50 against human fibroblasts is 10 µM. The results of
this study indicate that the new compounds are optimal anti-cancer leading compounds and merit
further studies to optimize their structure, detect their biotargets and in vivo activity.
2

Although a range of treatment options are available for cancer, chemotherapy is fraught with
significant levels of toxicity to healthy cells, and drug resistance develops in some treatment
regimes. To decrease the current cancer burden, drug discovery is directed at the development of
highly effective and potent medications with reduced side effects. 5-aminosalicylic acid (5-
ASA), as well as its prodrugs that are currently used in the management of inflammatory bowel
diseases have been shown recently to possess cancer chemopreventive and chemotherapeutic
1
properties. The mechanism of this activity is attributed to improved maintenance of genomic
2
stability that counteracts carcinogenesis, thus contributing to its chemopreventive and
3
,4
chemotherapeutic properties, in particular, against colorectal cancer. 1,2,3-triazolyl-
salicylamides exhibited antiproliferative activity as lavendustin mimetics and potent aurora
5
kinase inhibitors. Recently, it was suggested that the antioxidant properties of salicylate
6
derivatives is a possible mechanism of anti-inflammatory activity.
On the other hand, 2-arylaminothiazolidin-4-ones having 5-un/substituted benzylidenes were the
most promising in inhibiting growth of several human cancer cell lines but not normal fibroblasts
7
-13
in a dose dependent manner. Several mechanisms were suggested for these effects involving
1
4
reversible blockage of cell cycle progression at the G2/M phase border, induction of apoptosis,
1
5
antagonizing stimulatory effect of free fatty acids at cell proliferation, inhibition of translation
1
6
initiation, interaction with Sphigosine Kinase and non-membrane protein tyrosine phosphatase
17
(
SHP-2).
For complex diseases like cancer; a balanced modulation of several targets can provide advanced
therapeutic effects and a favorable side effects profile compared to the action of selective ligand.
Accordingly, it is thought of interest to accommodate thiazolin-4-one and 5-ASA moieties in a
single molecular framework as the key pharmacophore and screen the antiprolerative activity.
1
8
Interestingly, the target compounds can be considered as lavendustin analogs. Our design is
based, also, on an interesting SAR study in 2-amino-4-thiazolinones which allowed to identify
optimal H-bond donating OH substituent at para position of arylamino fragment, as well as small
19
lipophilic substituents of the benzylidene moiety at positions 3 and 4 are favored. Several
studies revealed that the presence and the nature of the moiety at position 5 of thiazolidinone
1
9-22
play the key role in realization of the pharmacological effects.
Accordingly, the structural
variations were selected by introducing different benzylidenes at that position.
3

The target compounds were synthesized as shown in Scheme 1 (see ESI for experimental
details). 5-ASA was chloroacetylated by heating with chloroacetyl chloride in dry benzene.
2
3
Heterocyclization of the product in the presence of ammonium thiocyanate in refluxing ethanol
efficiently produced methyl 2-hydroxy-5-[(4-oxo-4,5-dihydro-1,3-thiazol-2-yl)-amino]benzoate
2
4
(
1). The two active methylene protons appear as separate doublets at δ = 4.00 and 3.96 ppm.
The target compounds (2-19) were obtained by refluxing 1 with commercially available aromatic
aldehydes using a Knoevenagel condensation procedure in the presence of sodium acetate, in
glacial acetic acid. The purity of the synthesized compounds has been checked by TLC. The
1
structures of the synthesized compounds were confirmed by analytical and spectral data (IR , H,
1
3
25
1
C NMR and ESI-HRMS). In H NMR spectra of compounds 1-19 characteristic doubling of
the signals is seen that corresponds to the presence of tautomerism or syn/anti arrangement
rotamers. On the basis of spectra the correlation of the two isomers in the solution make
approximately 1:1 mixture. For example, NH prot ꢀꢁꢂꢃꢃꢄꢂꢅꢆꢁꢂꢆꢁꢇꢈ ꢁꢆꢉꢀꢊꢋꢄꢇꢆꢁꢂꢇꢁꢂꢌ ꢍꢇꢁꢁ
ꢃꢃꢓꢁꢂꢀꢔꢁꢁꢁꢁ12.45 ppm. The ꢕ-ꢖꢗꢖꢁꢓ ꢉꢄꢇꢘꢁꢙ ꢅꢓꢆꢁꢆꢍꢌꢆꢃꢄꢚꢇꢅꢍꢓꢁ ꢙꢁꢓꢍꢋꢇꢉꢃꢋꢄꢇꢆꢁꢂꢇꢁꢁꢁ7.05-7.55 ppm.
Only Z-isomers were obtained as in the Knoevenagel reaction, because it is thermodynamically
ꢎꢁ ꢁꢏꢏꢐꢑꢒꢁ
ꢎ
ꢎ
2
6
stable.
OH
OH
COOCH3
COOCH3
benzene
NH4SCN
ClCOCH Cl
2
reflux, 6 h
EtOH, reflux, 2h
NH2
HN
Cl
R
O
O
O
H COOC
3
N
H COOC
3
N
OHC
S
S
CH COOH, CH COONa
3
3
HO
HO
reflux, 24 h
NH
NH
R
2-19
1
2
: R = H; 3: R = 4-Me; 4: R = 4-OMe; 5: R = 4-NO ; 6: R = 4-Cl; 7: R = 2-OH; 8: R = 3-Cl; 9: R
2
=
=
2-OMe; 10: R = 4-Br; 11: R = 2-Cl; 12: R = 3-Br; 13: R = 4-NMe ; 14: R = 3,4-OCH O-; 15: R
2
2
3,4-di-OMe; 16: R = 4-OH; 17: R = 3-NO ; 18: R = 3,4,5-tri-OMe; 19: R = 4-F
2
Scheme 1. Synthesis of methyl 2-hydroxy-5-[(5-benzylidene -4-oxo-4,5-dihydro-1,3-thiazol-2-
yl)-amino]benzoates 2-19.
2
-Arylamino-2-thiazolin-4-ones and their 5-substituted derivatives can primarily display
amino/imino due to prototropic tautomerism. Additionally, both tautomeric forms may exist as a
4

mixture of two conformers (T-1, T-2 and T-3, T-4; Scheme 2), which are particularly stabilized
by the formation of intramolecular hydrogen bonds. It is worth noting that amino/imino
tautomerism in 2-amino(imino)-1,3-thiazolidin-4-one derivatives have been extensively
investigated. Results from these studies showed that the tautomer with the carbonyl–imine group
2
7
in the five-membered heterocyclic ring and an exocyclic amine N atom is predominant.
Similarly, X-Ray single crystal analysis of 1 revealed that the amino form is predominant and the
compound is crystallized with two independent molecules in the asymmetric unit that differ
2
4
primarily in the rotational orientation of the five-membered heterocyclic ring (Figure 1). This
finding was also studied by computational chemistry.
T-3 (S-cis)
T1 (S-trans)
Figure 1. The structures of the rotamers of compound 1; The asymmetric unit with labeling
2
4
scheme and 50% probability ellipsoids.
The possible conformational (S-trans and S-cis, such as T-1 and T-3 respectively) and the
configurational (E and Z such as T2 and T4 respectively) isomers are shown in Scheme 2. The
structures and the vibrational frequencies of all stable rotamers and tautomers have been
calculated. Final energies have been obtained and recorded in Table 1. The results show that the
rotamers T1 and T3 are almost of equal heat of formation and both are much more stable than
their corresponding tautomers T-2 and T-4, respectively. This finding explains why this
precursor 1 is found as inseparable 1:1 mixture of conformers (T-1 and T-3). To our knowledge
st
this is the 1 crystal structure shows conformers (not tautomers) and in equal ratio. Systematic
investigation of the reported X-ray structure shows that the two rotamors are stacked together
oppositely and face to face via the amino-thiazoline entities.
5

H CO
O
H3CO
HO
O
3
O
O
HO
N
HN
S
S
N
H
N
T-1
T-2
H CO
O
H3CO
O
3
HO
HO
S
S
O
O
N
N
N
N
H
T-3
T-4
H
H CO
3
O
HO
S
OH
N
N
T-5
Scheme 2. Tautomers and conformational ismoers of compound 1
Table 1.
Physicochemical parameters of minimized Tautomers and conformers of compound 1.
T-1 (S-trans)
0.263
T-2 (E)
0.323
T-3 (S-cis)
0.228
T-4 (Z)
0.341
T-5 (Z)
0.521
a
STR
b
BND
3.473
7.333
3.995
9.757
16.801
1.657
c
QQ
HF
-0.222
-10.567
-114.58
-1.296
-129.19
3.748
-12.883
-116.75
3.943
d
-129.29
171.23
e
DM
7.559
4.959
3.495
a
b
c
d
e
stretching energy. bending energy. core-core interaction. heat of formation. dipole
moment
A pair of T-1 and T-3 makes strong hydrogen bonds with another pair of T-3 and T-1 in which
there is strong hydrogen bonding between the NH of the N-cis conformer in a pair and the
thiazoline-N of the NH-trans, occupies the same plane, with the other pair, providing the crystal
lattice.
The molecular modeling of the tested compound was studied for each possible structure as fully
2
8,29
optimized at full self-consistent field (SCF) levels by using MOPAC;
orbital package implemented with molecular mechanics software MMX-PC.
a general molecular
3
0
6

The potential antiproliferative activity of all synthesized compounds (1-19) was preliminarily
evaluated in vitro at a single concentration of 10 µM against the breast cancer cell line (MCF-7),
3
1,32
using the Sulforhodamine B assay (SRB).
The effect of this concentration on cell survival is
given in Table 2 (see ESI for experimental details).
These results showed that several compounds exhibited strong growth inhibitory activities
against MCF-7, such as 3, 7, 10 and 13. These compounds were further selected for more
detailed investigation to obtain full dose response survival curves using different concentrations
(
0,001–10 µM) against four different human cancer cell lines from different histological
backgrounds (breast MCF-7, colon HCT-118, lung A549 and cervix HeLa).
Table 2.
Percent reduction in the survival of MCF7 cells after treatment with a single concentration (10
µM, 48 h)
b
Compound
DMSO
% of cells remaining survival
SD
8.3
12.0
8.5
4.0
2.9
5.0
4.0
5.0
4.5
6.0
2.4
8.7
6.2
4.8
4.2
4.8
7.0
7.3
11.7
8.2
1.8
a
100.0
97.0
67.8
17.8
26.0
73.9
28.0
16.5
65.9
70.0
19.0
85.0
68.0
16.2
28.0
26.6
93.5
82.2
73.3
86.0
4.0
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
8
9
c
Doxorubicin
a
b
Control cells treated with the vehicle, (DMSO) added as 0.1%. Each value is the average of
c
six readings. 10 µM Doxorubicin is used as an internal reference standard.
7

The effects of the compounds on the proliferation of a human normal fibroblast strain (F180)
was also used to test the effects of the compounds on normal cells. Doxorubicin was used in all
experiments as the reference standard because it is a wide spectrum anticancer agent that is
effective against different types of cancer. From the full dose-response curve, (Figures 1S-3S in
ESI), the respective IC50 (concentration of the compound that kills 50% of the cells after 48 h
incubation compared to untreated controls) was calculated and used as a parameter for the
antiproliferative activity of the compounds.
Results of the survival assay (Table 3 and Figures 1S-3S in ESI) showed that some compounds
have an IC50 comparable to doxorubicin on some tested cancer cell lines. Compounds 3 (IC50
.085 ± 0.01 µM) and 13 (IC50 = 0.31 ± 0.02 µM), for example, have an IC50 comparable to
=
0
doxorubicin on the Cervix (HeLa) and colon (HCT-116) cancer cell lines, respectively.
Compound 10 (IC50 = 0.07 ± 0.09 µM) has the same IC50 of doxorubicin on MCF-7.
The lung cancer cell line (A549) was more resistant to the four tested compounds than
doxorubicin. Generally, the four compounds were less effective on the lung adenocarcinoma cell
line (A549) than the other three cancer cell lines. This is in line with the fact that non-small cell
3
2
lung cancer cells (like the A549) are known to be resistant to chemotherapy.
Table 3.
IC50 values of compounds 3, 7, 10 and 13 against MCF-7, HCT-116, Hela, A549 and F118 as
determined based on sulforhodamine assay.
a
IC50 (µM)
Compd.
MCF-7
HCT-116
Hela
A549
F180
3
7
0.41 ± 0.06
0.5 ± 0.07
0.07 ± 0.00
0.63 ± 0.04
0.45 ± 0.06
3.44 ± 0.03
5.58 ± 0.04
0.31 ± 0.02
0.38 ± 0.02
0.085 ± 0.01 2.2 ± 0.28
1.05 ± 0.18
>10
1.39 ± 0.01
3.48 ± 0.15
0.18 ± 0.02
0.1 ± 0.01
>10
1
0
3
8.3 ± 0.62
2.4 ± 0.11
0.45 ± 0.05
10 ± 0.85
0.94 ± 0.08
0.35 ± 0.02
1
Doxorubicin 0.07 ± 0.00
a
Concentration required to decrease viability to 50% of control untreated cells; values are the
mean ± SD for n = 3 determinations each in triplicates.
8

The most interesting result was that the four compounds were less toxic to the normal fibroblast
strain (F180) than the doxorubicin. The IC50 of compound 10, for example, was about 28 times
higher than doxorubicin's IC50 on the normal fibroblasts which may indicate that these
compounds are safer than doxorubicin.
Based on the results presented in Tables 2 and 3, some preliminary structure–activity relationship
aspects can be deduced. This preliminary SAR study has focused on the effect of substitutent at
benzylidene ring on the antitumor activity. Incorporation of unsubstituted benzylidene moiety
has rendered the compound 2 with moderate activity. The data reveal that the activity is related
to the substituent at the benzylidene ring. Since fluorine has a size similar to those of hydrogen,
it is introduced as an isosteric to it. Fluorine substituent at the 4-position (compound 19), resulted
in a partial loss of the activity. In contrast, introduction of chlorine or bromine atom (more bulky
than fluorine) at this position (6 and 10) has caused a remarkable enhancement in the antitumor
activity. Interestingly, moving the chlorine from the 4- and 3-positions to the 2-position has
sharply decreased the antitumor activity. Accordingly, the activities of the halogenated members
were decreased in the order of 4-Br > 4-Cl > 3-Bꢅꢁ≈3-Cl > 2-Cl > 4-F for the MCF-7 cells. This
finding suggets that the incroporation of halogens into 4-position may be advantageous.
Interestingly, the introduction of 4-methyl or 4-dimethylamino (electron-donating group) at the
4
-position of benzylidene has enhanced the activity against the four tested cancer cell lines;
compounds 3 and 13, respectively. These compounds have represented the most active
derivatives against the breast cancer cell line MCF-7. The introduction of 4-methoxy (4)
decreased the activity while 4-hydroxy (16) showed a significant drop in activity. Surprisingly,
2
-hydroxy derivative (7) showed promising activity and was one of the most active compounds.
Based on this results, we can deduce that the substitution pattern on the benzylidene moiety is a
crucial element for the antitumor activity. The incorporation of electron donating groups, as the
4
-dimethylamino or 4-methyl group, is highly favorable and resulted in compounds with
promising activity; 3 and 13. Moreover, substitution with bulky electron withdrawing groups as
the 4-bromine has greatly enhanced the activity; 10. 4-Hydroxylation is completely unfavorable
while 2-hydroxylation provided the most active compound; 7. This may be due to intramolecular
interaction with the endocyclic N and/or S.
9

In the present study, nineteen 5-aminosalicylates incorporating thiazolin-4-ones (1-19) were
synthesized and their geometrical and rotational isomerism were studied by x-ray crystal study
and computational method. The compounds were evaluated for their antiproliverative activities
against four human cancer cell lines (MCF-7, HCT-118, HeLa and A549. From the structure
activity relationships (SARs) we can deduce that the benzylidene moiety is essential for activity.
The introduction of an electron donating or withdrawing bulky group at the 4-position of
benzylidene plays an important role in enhancing the antitumor activities. It was found that
compounds with a 4-methyl (3), 2-hydroxy (7), 4-bromo (10), p-dimethylamino (13) at
benzylidene ring have promising activity. These four compounds showed anti-proliferative
activity comparable to doxorubicin against MCF-7, HCT-118 and HeLa cells with lower
cytotoxicity to the normal fibroblasts. Accordingly, they are potential anticancer drug leads and
worth further detailed investigations to further optimize their structure and detect their
mechanism of action and their effects on animal/xenograft models to evaluate in vivo
bioavailability and chemotherapeutic potential.
Acknowledgements
This work was supported by Faculty of Pharmacy, Assiut University. We are grateful to Dr.
Mostafa H. Abdelrahman-Department of Chemistry, University of Aberdeen, UK- and to Dr.
Munkir Hossain-Institute of chemistry-Academia Sinica, Taiwan- for help in spectral data.
Supplementary information
Supplementary data associated with this article can be found, in the online version.
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4. Mohamed, S. K.; Mague, J. T.; Akkurt, M.; Abdu-Allah, H. H. M.; Albayati, M. R.
ActaCryst. 2015, E 71, o282.
5. (a) Synthesis of methyl 2-hydroxy-5-[(4,5-dihydro-4-oxo-1,3-thiazol-2-yl)-amino]benzoate
(
1). A solution of methyl 5-chloroacetamidosalicylate (2.3 g, 9.5 mmol) and ammonium
thiocyanate (1.5 g, 19.7 mmol) in 40 ml ethanol was refluxed for 2 h and allowed to stand
overnight. The mixture was evaporated and the residue was washed with water and the
recrystallized from ethanol/water to give the target com.p.ound (2.13 g, 85% yield); mp =
o
2
1
08-209 C; IR (KBr): 3250, 3085, 2915, 2770, 1671, 1628, 1595, 1568, 1511, 1479, 1433,
1
328, 1273, 1207, 824, 732. H NMR (400 MHz, DMSO-dꢑ)ꢁδ=ꢁꢏꢏꢐ7ꢏ,ꢁꢏꢏꢐꢏ2ꢁ(2*ꢆ,ꢁꢏH;ꢁ
NH), 10.40, 10.34 (2*s, 1H; OH), 8.15, 7.39 (2*d, J(H,H)= 2.8 Hz, 1H; ArH-6), 7.76, 7.19
(
2*dd, J(H,H)= 9.0, 2.8 Hz, 1H; ArH-4), 7.03-6.98 (m, 1H; ArH-3), 4.00, 3.96 (2*d,
13
J(H,H)= 15.8 Hz, 2H; CH
2
), 3.90, 3.88 (2*s, 3H; OCH ). C NMR (101 MHz, DMSO-d6)
3
δ=ꢁꢏ87ꢐ99,ꢁꢏ77ꢐ89,ꢁꢏꢑ8ꢐꢑ4,ꢁꢏꢕ7ꢐꢏꢏ,ꢁꢏꢕꢑꢐ79,ꢁꢏ3ꢒꢐ8ꢒ,ꢁꢏ29ꢐ9ꢑ,ꢁꢏ28ꢐꢒ3,ꢁꢏ22ꢐꢏꢑ,ꢁꢏ2ꢏꢐ43,ꢁꢏꢏ8ꢐ44,ꢁ
1
17.97, 113.29, 113.01, 52.63, 52.58, 38.47, 35.01. HRMS calcd for C11
H
11
N
2
4
O S (M +
+
H) , 267.0440; found, 267.0452; (b) General Procedure for Synthesis of methyl 2-hydroxy-
5
-[(5-benzylidene -4-oxo-4,5-dihydro-1,3-thiazol-2-yl)-amino]benzoate (2–19).
To a well-stirred solution of compound 1 (0.3 g, 1.13 mmol) in acetic acid (10 mL) buffered
with sodium acetate (0.18 g, 2.2 mmol), the appropriate arylaldehyde (1.6 mmol) was
12

added. The solution was refluxed overnight till the completion of the reaction as monitoring
by TLC, and then poured into ice-cold water. The precipitate was filtered, washed with
water, and the resulting crude product was purified by recrystallization from dioxane.
6. (a) Lesyk, R.; Zimenkovsky, B. Curr. Org. Chem. 2004, 8, 1547; (b) Havrylyuk, D.;
Zimenkovsky, B.; Vasylenko, O.; Zaprutko, L.; Gzella, A.; Lesyk, R. Eur. J. Med. Chem.
2
2
009, 44, 1396; (c) Lesyk, R.; Zimenkovsky, B.; Subtelna, I.; Nektegayev, I.; Kazmirchuk,
G. Acta Poloniae Pharmaceutica. Drug Res. 2003, 6, 457; (d) Bruno, G.; Costantino, L.;
Curinga, C.; Maccari, R.; Monforte, F.; Nicolo, F.; Ottana, R.; Vigorita, M. G. Bioorg.
Med. Chem. 2002, 10, 1077; (e) Vicini, P.; Geronikaki, A.; Incerti, M.; Zani, F.; Dearden, J.;
Hewitt, M. Bioorg. Med. Chem. 2008, 16, 3714.
2
2
2
3
7. Gzella, A. K.; Kowiel, M.; ꢗꢍꢆꢄł,A.; Wojtyr, M. N.; Lesyk, R. Acta Cryst. 2014, C70, 812.
8. Bingham, R. C.; Dewar, M. J. S.; Lo, D. H. J. Am. Chem. Soc. 1975, 97, 1302.
9. Bingham, R. C.; Dewar, M. J. S.; Lo, D. H. J. Am. Chem. Soc. 1975, 97, 1285.
0. QCM.P Program catalogue-computational chemistry software for IBM-PC and Compatible
Computers, QCPE, Indiana University, Bloomington, IN; 1992.
3
3
1. Skehan, P.; Storeng, R.; Scudiero, D.; Monks, A.; McMahon, J.; Vistica, D.; Warren, J. T.;
Bokesch, H.; Kenney, S.; Boyd, M. R. J. Natl. Cancer Inst. 1990, 82, 1107.
2. El-Awady, R. A.; Hersi, F.; Al-Tunaiji, H.; Saleh, E. M.; Abdel-Wahab, A. A.; Al Homssi,
A.; Suhail, M.; El-Serafi, A.; Al-Tel, T. Cancer Biol. Ther. 2015, 16, 1056.
13

Graphical Abstract
Design and synthesis of novel 5-aminosalicylate (5-ASA)- 4-thiazolinone hybrid derivatives
with promising antiproliferative activity
Hajjaj H. M. Abdu-Allah, Samia G. Abdel-Moty, Raafat El-Awady, Abdel-Nasser A. El-
Shorbagi