Synthesis and anticancer activity of some novel trifluoromethylquinolines carrying a biologically active benzenesulfonamide moiety

Article abstract of DOI:10.1016/j.ejmech.2013.08.048

Several trifluoromethylquinoline derivatives containing a biologically active benzenesulfonamide moiety 2-14, 16, urea derivatives 15, 17, 4-isothiocyanate 18 and the corresponding carbamimidothioic acid derivatives 19-30, were synthesized from the strategic starting material 4-chloro-7-trifluoromethylquinoline 1. The structures of the newly synthesized compounds were elucidated on the basis of elemental and spectral analyses. All the prepared compounds were evaluated for their in vitro anticancer activity against various cancer cell lines. Most of the synthesized compounds showed good activity, especially compound 15 which exhibited higher activity than the reference drug doxorubicin. In order to suggest the mechanism of action for their cytotoxic activity, molecular docking for all synthesized compounds was done on the active site of PI3K and good results were obtained.

Full text of DOI:10.1016/j.ejmech.2013.08.048

Accepted Manuscript
Synthesis and Anticancer Activity Of Some Novel Trifluoromethylquinolines Carrying
A Biologically Active Benzenesulfonamide Moiety
Mohammed S. Al-Dosari, Mostafa M. Ghorab, Mansour S. AlSaid, Yassin M. Nissan,
Abdulkareem B. Ahmed
PII:
S0223-5234(13)00566-7
10.1016/j.ejmech.2013.08.048
EJMECH 6396
DOI:
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 8 May 2013
Revised Date: 25 August 2013
Accepted Date: 28 August 2013
Please cite this article as: M.S. Al-Dosari, M.M. Ghorab, M.S. AlSaid, Y.M. Nissan, A.B. Ahmed,
Synthesis and Anticancer Activity Of Some Novel Trifluoromethylquinolines Carrying A Biologically
Active Benzenesulfonamide Moiety, European Journal of Medicinal Chemistry (2013), doi: 10.1016/
j.ejmech.2013.08.048.
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ACCEPTED MANUSCRIPT
HN
O
SH
O
S
O
S
NH2
NH
N
N
N
NH
HN
NH
H
O
O
F
F
F
F
N
F
F
1
5
21
IC50 = 18.39 µM (MDA-MB231)
IC50 =
1
2
1
1
3
7.89 µM (HT 1080)
7.62 µM (HepG2)
9.65 µM ( Lovo)
8.42 µM (AS49-Raw)
5.29 µM (Hela)
24.29µM (HT 1080)
33.48µM (HepG2)
23.91µM ( Lovo)
23.91µM (AS49-Raw)
23.91µM (Hela)
Most of the synthesized compounds showed good cytotoxic activity especially
compounds 15 and 21 on breast, lung, liver, colorectal, lung and Hela cancer cell lines

ACCEPTED MANUSCRIPT
Synthesis and Anticancer Activity Of Some Novel Trifluoromethylquinolines
Carrying A Biologically Active Benzenesulfonamide Moiety
a
*b
b
c
Mohammed S. Al-Dosari , Mostafa M. Ghorab , Mansour S. AlSaid ,Yassin M. Nissan ,
Abdulkareem B. Ahmed
a
a
Pharmacognosy Department, College of Pharmacy, King Saud University, P.O.Box 2457,
Riyadh 11451, Saudi Arabia
b
Medicinal, Aromatic and Poisonous Plants Research Center (MAPPRC), College of Pharmacy,
King Saud University, P.O.Box 2457, Riyadh 11451, Saudi Arabia
Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
c
*
Corresponding author: M.M. Ghorab, Professor of Applied Organic Chemistry, Medicinal,
Aromatic and Poisonous Plants Research Center (MAPPRC), College of Pharmacy, King Saud
University, P.O.Box 2457, Riyadh 11451, Saudi Arabia. Tel.: +966 534292860; fax: +966 01
4
670560. E-mail address: mmsghorab@yahoo.com.
1

ACCEPTED MANUSCRIPT
Abstract
Several
trifluoromethylquinoline
derivatives
containing
a
biologically
active
benzenesulfonamide moiety 2-14, 16, urea derivatives 15, 17, 4-isothiocyanate 18 and the
corresponding carbamimidothioic acid derivatives 19- 30, were synthesized from the strategic
starting material 4-chloro-7-trifluoromethylquinoline 1. The structures of the newly synthesized
compounds were elucidated on the basis of elemental and spectral analyses. All the prepared
compounds were evaluated for their in vitro anticancer activity against various cancer cell lines.
Most of the synthesized compounds showed good activity, especially compound 15 which
exhibited higher activity than the reference drug doxorubicin. In order to suggest the mechanism
of action for their cytotoxic activity, molecular docking for all synthesized compounds was done
on the active site of PI3K and good results were obtained.
Keywords: trifluoromethylquinoline, sulfonamide, carbamimidothioic acid, anticancer activity.
1
. Introduction
It is observed from the literature that many quinoline derivatives posses a wide range of
biological activities including anti-inflammatory [1], antileshmanial [2], antifungal [3],
antituberclosis [4], antimalarial [5,6] and anticancer activity [7-9]. On the other hand, quinoline
containing compounds have only been used for the treatment of malaria [10], beginning with
quinine, which is a 4,6-substitued quinoline. Recently, the antitumor activity of quinolines as
anticancer agents [11] and specially against breast cancer cell lines, with chloroquinoline being
the most apoptosis-inducing agent, has been reported [12]. All differentiation-inducing
quinolines caused growth suppression in MCF-7 and MCF 10 A cells. The mechanism of action
of the differentiation-inducing quinolines has been proposed to involve strong suppression of
E2F1 that inhibits growth by preventing cell cycle progression and fasters differentiation by
creating a permissive environment for cell differentiation [13]. It has been known that
aryl/heteroaryl sulfonamides may act as antitumor agents through a variety of mechanisms such
as cell cycle perturbation in the G1 phase, disruption of microtubule assembly, angiogenesis
inhibition, and functional suppression of the transcriptional activator NF-Y. Moreover, following
an extensive evaluation, numerous sulfonamides were found to act as carbonic anhydrase (CA)
2

ACCEPTED MANUSCRIPT
inhibitors[14-16]. Recently, combination of quinoline nuclues with sulfonamide moieties has
received a great attention in seeking for novel anticancer agents [17]. Several quinoline
sulfonamide derivatives showed potent anticancer activity as phosphoinisitol kinase (PI3K)
inhibitors [17]. In addition, the special properties of the fluorine atom, such as a strong
electronegativity, small size and the low polariazability of the C-F bond, can have a considerable
impact on the behavior of a molecule in a biological environment [18-20]. The incorporation of
electronic, lipophilic and steric parameters , all of which can critically influence both the
pharmacodynamic and pharmacokinetics properties of drugs. Bioisosteric substitution for
hydrogens by fluorines is therefore, an important strategy for incorporation of a group capable of
reinforcing drug-receptor interactions (electronic modulation), aiding translocation across lipid
bilayers or absorption (lipophilic modulation) and inducing conformational changes/ blocking
metabolism (steric parameters) [21]. On the basis of these reports and in continuation of our
research program [22-35] on the synthesis of novel heterocyclic compounds exhibiting
anticancer activity, we reported here the synthesis of novel compounds containing quinoline
derivatives carrying a biologically active benzenesulfonamide moiety 2- 30 to evaluate their
anticancer activity hoping to discover a new series of anticancer agent that may add to the
continuous search for better anticancer agents with less side effects.
2
. Results and discussion
2
.1.Chemistry
The aim of the this work was to design and synthesize a new series of trifluoromethylquinoline
derivatives carrying a biologically active benzenesulfonamide and to evaluate their anticancer
activity. Thus, the interaction of 4-chloro-7-trifluoromethylquinoline 1 with several sulfa drugs
in dry N,N'-dimethylformamide afforded the corresponding 7-trifluoromethylquinoline
sulfonamide derivatives 2-14. The structures of the formed compounds were confirmed on the
basis of elemental analysis and spectral data. In addition the structure compound 2 was
confirmed through x-ray crystallography [36] (Figure 1).
1
IR spectra for compounds 2-14 showed absorption bands for (NH), (CH aromatic) and (SO ). H-
2
NMR spectra exhibited a doublet signals at 6.6 - 8.6 ppm corresponding to (2CH) of quinoline
3

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and singlet signals at 8.5-9.7 ppm corresponding to (NH) which were exchanged upon
deuteration.
Interaction of compound 2 with phenyl isocyanate in dry N,N'-dimethylformamide in the
prescence of anhydrous potassium carbonate furnished the corresponding phenyl urea derivative
-1
1
5 in good yeild. IR spectrum of compound 15 revealed bands at 3200, 3163 and 3123cm
-1
-1
1
(
NH), 1664 cm (C=O) and 1379, 1163 cm (SO ). H-NMR spectrum of 15 showed two
2
doublets at 6.9, 8.6 ppm for 2CH of quinoline and a singlet at 8.5 ppm due to 2NH of urea group.
On the other hand, when compound 1 was reacted with sulfanilamide in dry DMF in the
prescence of anhydrous potassium carbonate [37], the corresponding 4-amino-N-(7-
(trifluoromethyl)quinolin-4-yl)benzenesulfonamide 16 was obtained. The structure of compound
1
6 was proved based on analytical and spectral data. IR spectrum of compound 16 revealed
-1
-1
-1
1
bands at 3483, 3355 and 3222 cm (NH,NH ), 1596 cm (C=N), 1372 and 1177 cm (SO ). H-
2
2
NMR spectrum exhibited a singlet at 6.7 ppm due to NH group and two doublets at 6.8 and 8.5
2
ppm corresponding to 2CH of quinoline. Interaction of compound 16 with phenyl isocyanate in
dry DMF gave the coressponding ureido derivative 17. IR spectrum of 17 exhibited bands at
-1
-1
-1
-
3
420, 3386 and 3210 cm (NH), 1668 cm (C=O), 1625 cm (C=N), 1398 and 1155 cm
1
1
(
SO ). H-NMR spectrum of 17 showed a singlet at 8.8 ppm for 2NH of urea moiety. In
2
addition, it was aimed to prepare the isothiocyanato intermediate 18 as isothiocyante derivatives
are useful and widely used building blocks in the synthesis of nitrogen, sulfur and oxygen
heterocylic compounds and organometallics of academic and pharmaceutical and industrial
interest. Thus, interaction of compound 1 with ammonium thiocyanate in dry acetone under
reflux for 1hr gave the corresponding 4-isothiocyanato derivative 18.This method led to a higher
overall yield and shorter working time compared to the reported method that was using silver
-1
thiocyanate in dry toulene [38]. IR spectrum of 18 revealed a new band at 2059 cm for
1
(
N=C=S). H-NMR spectrum of 18 revealed two doublets at 7.8 and 9.1 ppm for 2CH of
quinoline.
Finally, the carbamimidothioic acid derivatives 19- 30 were achieved by treatment of
isothiocyanato quinoline derivative 18 with several sulfa drugs in dry DMF containing a catalytic
amount of triethylamine. The structures of the synthesized compounds 19-30 were confirmed on
the basis of analytical and spectral data. IR spectra of these compounds revealed the abscence of
4

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1
(
N=C=S) band and the appearance of new bands corresponding to (NH) and (C=N). H-NMR
spectra for these compounds showed singlet signals at 2.5-2.7 ppm corresponding to SH group.
2
.2. Molecular docking
Almost 20 years of cancer biology and genomic studies have identified phosphoinositide 3-
kinase (PI3K) and the PI3K pathway as important players in tumor onset and maintenance. PI3K
is therefore considered a well-validated target for cancer treatment, and hence the demand for
inhibitors with drug-like properties was highly anticipated 5 years ago [39].
Based on the previous findings and as a trial to suggest the mechanism of action of the cytotoxic
activity for the synthesized compounds docking of all newly synthesized compounds was done
on the active site of PI3K.
The protein data bank file (PDB: 3S2A) was selected for this purpose. The file contains PI3K
enzyme co-crystallized with a quinoline ligand. All docking procedures were achieved by MOE
(Molecular Operating Environment) software 10.2008 provided by chemical computing group,
Canada. Docking on the active site of PI3K enzyme was performed for all synthesized
compounds.
Docking protocol was verified by redocking of the co-crystallized ligand in the vicinity of the
active site of the enzyme with energy score (S) = -29.8249 Kcal/mol and root mean standard
deviation (RMSD) = 1.9094 (Figure 2). The quinoline ligand interacts with the active site of
o
PI3K by six interactions: Val 882 with a hydrogen bond of 2.90 A , Tyr 867 with a hydrogen
o
o
bond of 3.33 A , Asp 864 with a hydrogen bond of 3.33 A , Lys 833 with a hydrogen bond of
o
o
o
3
.33 A , Ser 806 with a hydrogen bond of 3.74 A and Asp 841 with a hydrogen bond of 2.79 A
through a water molecule. All synthesized compounds were fit to the active site of PI3K enzyme
with good energy scores (S) suggesting activity as PI3K inhibitors. Energy scores (S) and amino
acid interactions for the synthesized compounds were listed in (Table 1). Compound 29 gave the
o
best energy score (S) = -27.2076 and interacted with Lys 808 with a hydrogen bond of 3.65 A ,
o
Lys 890 with a hydrogen bond of 2.92 A and Asp 841(through a water molecule) with a
o
hydrogen bond of 3.08 A (Figure 3).
2
.3. In vitro antitumor activity
5

ACCEPTED MANUSCRIPT
The newly synthesized compounds were evaluated for their in vitro cytotoxic activity against
human breast cancer cell line ( MDA-MB231), lung cancer cell line (AS49- Raw), Hela cancer
cell line, colorectal cell line (Lovo), skin cancer cell line (HT-1080) and liver cancer cell line
(
HepG ). Doxorubicin which is a known and effective anticancer agent was used as the reference
2
drug in this study. The relationship between surviving fraction and drug concentration was
plotted to obtain the survival curve of cancer cell lines. The response parameter calculated was
the IC50 value, which corresponds to the concentration required for 50% inhibition of cell
viability. Table 2 shows the in vitro cytotoxic activity of the newly synthesized compounds
where all compounds exhibited good activity compared to the reference drugs in case of human
breast cancer cell line ( MDA-MB231) except compounds 11, 13 and 21. On the other hand, all
the synthesized compounds exhibited good activity on skin cancer cell line (HT-1080), while
only compound 12 was inactive on lung cancer cell line (AS49-Raw lung). The cytotoxic activity
on Hela cell line was moderate for most of the synthesized compounds except for compounds 3,
6
, 11, 14, 23, 26 and 30 which were inactive. In case of colorectal cell line (Lovo), all
compounds showed good to moderate activity except for compounds 8, 11 and 22. Finally, the
activity on liver cell lines (HepG ) was moderate except for compounds 4, 8, 10, 11, 12, 17 and
2
2
7.
Compound 15 which is the phenylureido derivative was the most active compound on breast
cell line cancer (MDA-MB231) with IC value of 18.39 µM. The sulfapyridine derivative 9
5
0
exhibited a nearly similar IC value of 18.40 µM while compounds 24, 23, 4, 27, 16 showed
5
0
IC50 values of 24.39, 27.94, 28.83, 29.78 and 30.95 µM, respectively better than that of
Doxorubicin on the same cell line with IC value of 33.98 µM. Also compound 15 was the most
5
0
active compound on colorectal cell line cancer (Lovo) with IC50 value of 19.65 µM, while
compounds 9 and 21 showed IC values of 20.22 and 23.91 µM, respectively, which were
5
0
better than that of Doxorubicin on the same cell line with IC value of 24.33 µM. Compound 15
5
0
continues to be the most active compound on liver cancer cell line (HepG ) with IC value of
2
50
2
7.62 µM close to that of Doxorubicin on the same cell line with Ic50 value of 27.11 µM. On
lung cancer cell line (AS49- Raw), also compound 15 was the most active compound with IC50
value of 18.42 µM while compounds 21, 17, 24, 16, 9 and 27 exhibited IC values of 23.91,
5
0
2
4.50, 27.15, 29.23, 30.38 and 31.03 µM, respectively, which were better of that of Doxorubicin
on the same cell line with IC value of 32.78 µM. Compound 15 was still the most active
5
0
6

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compound on skin cancer cell line (HT-1080) with IC value of 17.89 µM which was better than
5
0
that of Doxorubicin with IC50 value of 19.22 µM. The cytotoxic activity on Hela cell line
revealed that compound 21 showed IC value of 23.01 µM, while, compound 15 exhibited IC
50
5
0
value of 35.29 µM while Doxorubicin showed IC value of 30.21 µM.
5
0
It was obvious from the aforementioned results that the phenylureido derivative 15 was in
general the best compound on most cell lines except for Hela cell line. Figure 4 illustrate the 3D
interaction of compound 15 on the active site of (PI3K) enzyme. Neither the subtituted or
unsubstituted sulfonamide derivatives 2- 14, 16 and 17 nor the carbamimidothioic acid
derivatives 19-30 showed better activity except for compound 21 on Hela cell line.
Conclusion
Quinolinesulfonamide derivatives could represent a promising new class for anticancer agents
as illustrated in this research for its promising cytotoxic activity on breast, skin, colorectal, liver ,
Hela and lung cancer cell lines. Compound 15 was the most active compound, which showed
higher activity than the reference drug Doxorubicin as positive control. The mechanism of action
of this cytotoxic activity could be suggested to be PI3K inhibitors due to the promising results
from molecular docking on the active site of this enzyme. Further investigation to the mechanism
of action should be conducted on next researches to confirm this mechanism of action urged by
the promising in vitro antitumor activity.
3
.Experimental
3
.1. Chemistry
The starting material 4-chloro-7-trifluoromethylquinoline 1 and all sulfa- drugs were purchased
from Sigma-Aldrich. Melting points were determined on an electrothermal melting point
apparatus (BUCHI melting point B-545- Switzerland) and were uncorrected. Precoated Silica gel
plates (Kiesel gel 0.25 mm, 60 G F 254, Merck) were used for thin layer chromatography (TLC).
The developing solvent system was chloroform/ methanol (10:3) and the spot were detected by
ultraviolet light. Infrared (IR) spectra (KBr disc) were recorded on FT-IR spectrophotometer
(Perkin Elmer) at the research Centre, College of Pharmacy, King Saud University, Saudi
1
Arabia. H-NMR spectra were scanned in dimethylsulfoxide (DMSO-D ) on
NMR
6
1
13
spectrophotometer (Bruker AXS Inc.) operating at 500 MHz for H and 125.76 MHz for C at
7

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the aforementioned
Research Center. Chemical shifts are expressed in δ values (ppm) relative
to tetramethylsilane (TMS) as an internal standard. Exchangeable protons were confirmed by
addition of drop of D O. Elemental analyses were done on model 2400 CHNSO analyzer
2
(Perkin Elmer).
3
.1.1. General procedure for the synthesis of compounds 2-14
A mixture of 1 (2.31 g, 0.01 mol.) and the corresponding sulfa drugs (0.012 mol.) in dry DMF
20 mL) was refluxed for 12h. The solid obtained after concentration was filtered and
crystallized from dioxane to give 2-14, respectively.
(
3
.1.1.2. 4-(7-(Trifluoromethyl)quinolin-4-ylamino)benzenesulfonamide 2
o
-1
Yellow crystals, Yield 89 %, melting point 272.4 C. IR: υ ./cm 3317, 3300, 3290 (NH,
max
1
NH ), 3071(CH arom.), 1585 (C=N) and 1381, 1157 (SO . H-NMR (DMSO-d D O) δ: 7.3, 8.6
2
2)
6,
2
(
2d, 2H, 2CH quinoline, J= 7.2 Hz), 7.5-8.5 (m, 9H, Ar-H + SO NH ), 9.5(s, 1H, NH, D O-
2 2 2
1
3
exchangeable). C-NMR (DMSO-d ) δ: 120.1, 120.7 (2), 122.3, 122.9, 124.5, 125.1, 127.2(2),
6
1
5
29.5, 129.7, 138.0, 143.8, 146.3, 148.0, 151.8. Anal. Calcd. for C H F N O S (367.35): C,
16 12 3 3 2
2.31; H, 3.29; N, 11.44. Found: C, 53.59; H, 3.61; N, 11.11.
3
.1.1.3. N-(4-(7-(trifluoromethyl)quinolin-4-ylamino)phenylsulfonyl)acetamide 3
o
-1
Yellow powder, Yield 82 %, melting point >350 C. IR: υ ./cm 3280, 3176 (2NH), 3067 (CH
max
1
arom.), 2970, 2836 (CH aliph.), 1696 (C=O), 1610 (C=N), 1396, 1155 (SO ). H-NMR (DMSO-
2
d D O) δ: 3.0(s, 3H, COCH ), 6.9, 8.6 (2d, 2H, 2CH quinoline, J= 7.3 Hz), 7.0-8.2 (m, 8H, Ar-
6
,
2
3
1
3
H+ SO NH), 8.5 (s, 1H, NH, D O-exchangeable). C-NMR (DMSO-d ) δ: 22.0, 119.3, 120.7
2
2
6
(2), 123.9, 125.1, 126.7, 127.7, 128.7 (2), 129.0, 129.2, 130.0, 148.3(3), 151.8, 156.4. Anal.
Calcd. for C H F N O S (409.38): C, 52.81; H, 3.45; N, 10.26. Found: C, 52.62; H, 3.19; N,
1
8
14
3
3
3
1
0.58.
3
.1.1.4. N-carbamimidoyl-4-(7-(trifluoromethyl)quinolin-4-ylamino)benzenesulfonamide 4
o
-1
Yellow powder, Yield 79 %, melting point 304.0 C. IR: υ ./cm 3454, 3440, 3344 (NH, NH ),
max
2
1
3
056 (CH arom.), 1635 (C=N), 1382, 1138 (SO ). H-NMR (DMSO-d D O) δ: 6.5 (s, 2H, NH ,
2 6, 2 2
D O-exchangeable), 7.2, 8.6 (2d, 2H, 2CH quinoline, J= 7.1 Hz), 7.4-8.2 (m, 8H, Ar-H+
2
8

ACCEPTED MANUSCRIPT
1
3
SO NH ), 9.5 (s, 1H, NHPh, D O-exchangeable). C-NMR (DMSO-d ) δ: 116.6, 118.6(2),
2
2
2
6
1
20.7, 122.1, 122.8, 124.5, 128.0(2), 129.6, 129.8, 130.1, 146.8, 147.4, 151.9. 152.3, 159.9.
Anal. Calcd. for C H F N O S (409.39): C, 49.88; H, 3.45; N, 17.11. Found: C, 49.59; H, 3.19;
1
7
14
3
5
2
N, 17.39.
3
.1.1.5. N-(3-methylisoxazol-5-yl)-4-(7-(trifluoromethyl)quinolin-4-ylamino)benzenesulfonamide
5
o
-1
Yellow powder, Yield 91 %, melting point 161.6 C. IR: υ ./cm 3292, 3190 (NH), 3077 (CH
max
1
arom.), 2960, 2840 (CH aliph.), 1616 (C=N), 1381, 1155 (SO ). H-NMR (DMSO-d D O) δ: 2.2
2
6,
2
(
s, 3H, CH ), 6.9 (s, 1H, CH isoxazole), 7.2, 6.8 (2d, 2H, 2CH quinoline, J= 7.4 Hz), 7.3-8.3 (m,
3
1
3
8
1
1
1
H, Ar-H + SO NH), 9.7 (s, 1H, NHPh, D O-exchangeable). C-NMR (DMSO-d ) δ: 12.0,
2 2 6
04.7, 119.8, 120.9 (2), 121.1, 122.5, 122.8, 125.8, 128.5 (2), 129.9, 130.2, 132.6, 146.4, 147.4,
51.2, 151.7, 162.2, 170.2. Anal. Calcd. for C H F N O S (448.42): C, 53.57; H, 3.37; N,
20
15
3
4
3
2.49. Found: C, 53.21; H, 3.09; N, 12.72.
3
.1.1.6. N-(3,4-dimethylisoxazol-5-yl)-4-(7-(trifluoromethyl)quinolin-4-
ylamino)benzenesulfonamide 6
o
-1
Orange powder, Yield 89 %, melting point 157.5 C. IR: υ ./cm 3372, 3280 (2NH), 3061 (CH
max
1
arom.), 2940, 2860 (CH aliph.), 1629 (C=N), 1381, 1157 (SO ). H-NMR (DMSO-d D O) δ:
2
6,
2
2
.4 (s, 6H, 2CH ), 7.3, 8. 6 (2d, 2H, 2CH quinoline, J= 7.0 Hz), 7.4-8.5 (m, 8H, Ar-H + SO NH),
3 2
1
3
9
.5 (s, 1H, NH, D O-exchangeable). C-NMR (DMSO-d ) δ: 8.6, 10.3, 104.7, 119.9, 120.6 (2),
2 6
1
22.5, 122.8, 124.9, 125.6, 129.6 (2), 129.8, 130.3, 137.2, 145.3, 146.9, 147.2, 151.5, 159.6,
62.2. Anal. Calcd. for C H F N O S (462.44): C, 54.54; H, 3.71; N, 12.12. Found: C, 54.81;
1
21
17
3
4
3
H, 3.47; N, 12.41.
3
.1.1.7. N-(1-phenyl-1H-pyrazol-5-yl)-4-(7-(trifluoromethyl)quinolin-4-
ylamino)benzenesulfonamide 7
o
-1
Orange powder, Yield 76 %, melting point 153.6 C. IR: υ ./cm 3481, 3210 (NH), 3046 (CH
max
1
arom.), 1624 (C=N), 1381, 1153 (SO ). H-NMR (DMSO-d D O) δ: 6.5 (d, 2H, 2CH pyrazole,
2
6,
2
J= 7.8 Hz), 7.3, 8.6 (2d, 2H, 2CH quinoline, J= 7.4 Hz), 7.4-8.5 (m, 13H, Ar-H + SO NH), 8.7
2
1
3
(
s, 1H, NH, D O-exchangeable). C-NMR (DMSO-d ) δ: 102.5, 119.3, 120.8 (2), 123.8 (2),
2
6
9

ACCEPTED MANUSCRIPT
1
1
1
24.1 (2), 125.1, 126.3, 126.5, 127.3 (2), 128.8, 129.3 (2), 129.6, 130.2, 135.1, 135.2, 147.4,
49.6, 152.0, 153.5, 162.0. Anal. Calcd. for C H F lN O S (509.50): C, 58.93; H, 3.56; N,
25
18
3
5
2
3.75. Found: C, 58.69; H, 3.29; N, 13.99.
3
.1.1.8. N-(thiazol-2-yl)-4-(7-(trifluoromethyl)quinolin-4-ylamino)benzenesulfonamide 8
o
-1
Yellow powder, Yield 79 %, melting point 169.8 C. IR: υ ./cm 3410, 3260 (NH), 3100 (CH
max
1
arom.), 1577 (C=N), 1381, 1141 (SO ). H-NMR (DMSO-d D O) δ: 6.8, 8.6 (2d, 2H, 2CH
2
6,
2
quinoline, J= 7.1 Hz), 7.2-8.3 (m, 10H, Ar-H + SO NH), 8.7 (s, 1H, NH, D O-exchangeable).
2
2
1
3
C-NMR (DMSO-d ) δ: 116.7, 118.7(2), 121.0, 121.8, 122.7, 124.2, 124.6, 127.7(2), 129.9,
6
1
30.4, 136.7, 143.3, 145.7, 147.9, 150.6, 160.0, 168.7. Anal. Calcd. for C H F N O S
2 2
19
13
3
4
(450.46): C, 50.66; H, 2.91; N, 12.44. Found: C, 50.36; H, 3.19; N, 12.13.
3
.1.1.9. N-(pyridin-2-yl)-4-(7-(trifluoromethyl)quinolin-4-ylamino)benzenesulfonamide 9
o
-1
Yellow powder, Yield 84 %, melting point 166.5 C. IR: υ ./cm 3340, 3210 (NH), 3078 (CH
max
1
arom.), 1635 (C=N), 1381, 1138 (SO ). H-NMR (DMSO-d D O) δ: 6.5-7.0 (m, 2CH, pyridine),
2
6,
2
7
.1, 8.1 (2d, 2CH, pyridine, J= 7.6, 8.1 Hz), 7.2, 8.6 (2d, 2H, 2CH quinoline, J= 7.8 Hz), 7.3-8.3
1
3
(
m, 8H, Ar-H+ SO NH), 8.7 (s, 1H, NH, D O-exchangeable). C-NMR (DMSO-d ) δ: 112.0,
2 2 6
1
13.6, 115.6, 118.7(2), 121.8, 122.7, 124.7, 124.9, 128.8(2), 129.9, 130.7, 136.3, 140.2, 141.4,
43.5, 145.6, 147.9, 150.5, 153.0. Anal. Calcd. for C H F N O S (444.43): C, 56.75; H, 3.40;
1
2
1
15
3
4
2
N, 12.61. Found: C, 56.48; H, 3.17; N, 12.97.
3
.1.1.10. N-(pyrimidin-2-yl)-4-(7-(trifluoromethyl)quinolin-4-ylamino)benzenesulfonamide 10
o
-1
Orange powder, Yield 77 %, melting point 271.9 C. IR: υ ./cm 3462, 3228 (NH), 3058 (CH
max
1
arom.), 1577 (C=N), 1381, 1161 (SO ). H-NMR (DMSO-d D O) δ: 6.9, 8.6 (2d, 2H, 2CH
2
6,
2
quinoline, J= 7.7 Hz), 7.0- 8.4 (m, 9H, Ar-H + CH pyrimidine + SO NH), 8.5,8.7 (2d, 2H, 2CH
2
1
3
pyrimidine, J= 7.5 Hz), 8.8 (s, 1H, NH, D O-exchangeable). C-NMR (DMSO-d ) δ: 105.8,
2
6
1
1
1
15.7, 118.5(2), 122.4, 122.8, 124.8, 127.1, 129.7(2), 129.9, 130.2, 134.5, 147.5, 152.0, 153.0,
56.9, 158.3, 160.2, 162.2. Anal. Calcd. for C H F N O S (445.42): C, 53.93; H, 3.17; N,
20
14
3
5
2
5.72. Found: C, 53.58; H, 3.49; N, 15.44.
1
0

ACCEPTED MANUSCRIPT
3
.1.1.11. N-(4-methylpyrimidin-2-yl)-4-(7-(trifluoromethyl)quinolin-4-
ylamino)benzenesulfonamide 11
o
-1
Brown powder, Yield 69 %, melting point 154.1 C. IR: υ ./cm 3387, 3294 (2NH), 3081 (CH
max
1
arom.), 2930, 2883 (CH aliph.), 1585 (C=N), 1381, 1157 (SO ). H-NMR (DMSO-d D O) δ:
2
6,
2
2
.3 (s, 3H, CH ), 6.8, 8.2 (2d, 2H, 2CH pyrimidine, J= 7.7, 7.8 Hz), 6.9, 8.6 (2d, 2H, 2CH
3
1
3
quinoline, J=7.5 Hz), 7.3-8.3 (m, 8H, Ar-H+ SO NH), 8.7 (s, 1H, NH, D O-exchangeable). C-
2
2
NMR (DMSO-d ) δ: 23.2, 111.9, 114.7, 119.6 (2), 122.8, 124.7, 125.6, 127.1, 129.1(2), 129.9,
6
1
30.1, 134.0, 144.5, 146.8, 151.5, 156.5, 157.5, 162.2, 168.2. Anal. Calcd. for C H F N O S
21 16 3 5 2
(459.44): C, 54.90; H, 3.51; N, 15.24. Found: C, 54.66; H, 3.27; N, 15.52.
3
.1.1.12. N-(4,6-dimethylpyrimidin-2-yl)-4-(7-(trifluoromethyl)quinolin-4-
ylamino)benzenesulfonamide 12
o
-1
Brown powder, Yield 80 %, melting point 153.9 C. IR: υmax./cm 3420, 3260 (NH), 3091 (CH
1
arom.), 2946, 2830 (CH aliph.), 1598 (C=N), 1381, 1159 (SO ). H-NMR (DMSO-d D O) δ:
2
6,
2
2
8
.4 (s, 6H, 2CH ), 6.7 (s, 1H, CH pyrimidine), 7.3, 8.6 (2d, 2H, 2CH quinoline, J=7.9 Hz) 7.4-
3
1
3
.5 (m, 8H, Ar-H + SO NH), 8.7 (s, 1H, NH, D O-exchangeable). C-NMR (DMSO-d ) δ: 22.8
2
2
6
(2), 105.4, 113.4, 119.5 (2), 122.2, 122.8, 124.5, 125.6, 129.8 (2), 130.1, 130.2, 134.3, 146.8,
1
3
49.9, 151.6, 156.2, 162.2 (2), 167.3. Anal. Calcd. for C H F N O S (473.47): C, 55.81; H,
22 18 3 5 2
.83; N, 14.79. Found: C, 55.54; H, 3.59; N, 14.44.
3
.1.1.13. N-(2,6-dimethoxypyrimidin-4-yl)-4-(7-(trifluoromethyl)quinolin-4-ylamino)benzene-
esulfonamide 13
o
-1
Brown powder, Yield 76 %, melting point 204.9 C. IR: υmax./cm 3253, 3221 (NH), 3074 (CH
1
arom.), 2946, 2862 (CH aliph.), 1581 (C=N), 1381, 1147 (SO ). H-NMR (DMSO-d D O) δ:
2
6,
2
3
7
5
1
3
.8 (s, 6H, 2OCH ), 5.8 (s, 1H, CH pyrimidine), 6.6, 8.6 (2d, 2H, 2CH quinoline, J= 7.7 Hz),
3
1
3
.3-8.4 (m, 8H, Ar-H + SO NH), 8.9 (s, 1H, NH, D O-exchangeable). C-NMR (DMSO-d ) δ:
2
2
6
4.3(2), 89.6, 122.4, 120.1(2), 122.0, 124.9, 126.3, 127.3, 128.6 (2), 128.9, 129.3, 130.4, 146.7,
49.4, 152.6, 157.9, 162.2, 163.3, 171.8. Anal. Calcd. for C H F N O S (505.47): C, 52.28; H,
2
2
18
3
5
4
.59; N, 13.86. Found: C, 52.49; H, 3.26; N, 13.49.
1
1

ACCEPTED MANUSCRIPT
3
.1.1.14. N-(5,6-dimethoxypyrimidin-4-yl)-4-(7-(trifluoromethyl)quinolin-4-ylamino)benzene-
sulfonamide 14
o
-1
Brown powder, Yield 69 %, melting point >350 C. IR: υmax./cm 3406, 3240 (NH), 3091 (CH
1
arom.), 2920, 2860 (CH aliph.), 1622 (C=N), 1381, 1156 (SO ). H-NMR (DMSO-d D O) δ:
2
6,
2
3
.6 (s, 6H, 2OCH ), 6.6, 8.6 (2d, 2H, 2CH quinoline, J= 7.1 Hz), 7.0-8.3 (m, 9H, Ar-H + CH
3
1
3
pyrimidine + SO NH), 8.7 (s, 1H, NH, D O-exchangeable). C-NMR (DMSO-d ) δ: 58.1(2),
2
2
6
1
16.0, 118.3(2), 122.8, 123.6, 124.0, 125.6, 127.6 (2), 129.8, 130.1, 132.6, 134.3, 143.2, 145.7,
48.3, 150.0, 152.9, 158.6, 169.2. Anal. Calcd. for C H F N O S (505.47): C, 52.28; H, 3.59;
1
2
2
18
3
5
4
N, 13.86. Found: C, 52.48; H, 3.23; N, 13.60.
3
.1.1.15. N-(phenylcarbamoyl)-4-(7-(trifluoromethyl)quinolin-4-ylamino)benzenesulfonamide 15
Dark brown powder, A mixture of 2 (3.6 g, 0.01 mol.) and phenyl isocyanate (1.21 g, 0.01 mol.)
in dry DMF (30 mL) containing anhydrous K CO (1 g) was refluxed for 17h. The reaction
2
3
mixture was cooled and poured onto ice/ water. The obtained solid was filtered and crystallized
o
-1
from acetic acid to give 15. Yield 84%, melting point 254.5 C, IR: ν /cm 3200, 3163, 3123
max
1
(
NH), 3064 (CH arom.), 1664 (C=O), 1575 (C=N), 1379, 1163 (SO ). H-NMR (DMSO-d D O)
2
6
2
δ: 6.9, 8.6 (2d, 2H, 2CH quinoline, J=7.5 Hz), 7.0-8.4 (m, 12 H, Ar-H), 8.5 (s, 2H, 2NHCO, D O
2
1
3
exchangeable), 8.7 (s, 1H, NH, D O exchangeable). C-NMR (DMSO-d ) δ: 119.5, 120.1(2),
2
6
1
21.7, 122.7 (2), 124.3, 125.1, 126.0, 126.8,127.4 (2), 129.0, 129.4 (2), 129.5, 129.8, 140.0,
47.9, 148.0, 148.3, 152.3, 162.2. Anal. Calcd. for C H F N O S (486.47): C, 56.79; H, 3.52;
1
2
3
17
3
4
3
N, 11.52. Found: C, 56.44; H, 3.76; N, 11.29.
3
.1.2. 4-Amino-N-(7-(trifluoromethyl)quinolin-4-yl)benzenesulfonamide 16
A mixture of 1 (2.31 g, 0.01 mol.) and sulfanilamide (1.72 g, 0.01 mol.) in dry DMF (30 mL)
containing anhydrous K CO (1 g) was refluxed for 10h. The reaction mixture was poured onto
2
3
ice/water and the obtained solid was crystallized from dioxane to give 16. Yellow powder, Yield
o
-1
8
8%, melting point 211.0 C, IR: ν /cm 3483, 3355, 3222 (NH, NH ), 3100 (CH arom.), 1596
max 2
1
(
C=N), 1372, 1177 (SO ). H-NMR (DMSO-d D O) δ: 6.7 (s, 2H, NH , D O exchangeable),
2 6 2 2 2
1
3
6
.8, 8.5 (2d, 2H, 2CH quinoline, J=7.7 Hz), 7.0-8.3 (m, 8 H, Ar-H + SO NH). C-NMR
2
(
DMSO-d ) δ: 116.5, 118.8 (2), 122.2, 124.4, 125.2, 126.6, 128.0 (2), 130.0, 131.3, 132.1, 141.8,
6
1
2

ACCEPTED MANUSCRIPT
1
50.1, 154.0, 158.8. Anal. Calcd. for C H F N O S (367.35): C, 52.31; H, 3.29; N, 11.44.
16
12
3
3
2
Found: C, 52.55; H, 3.05; N, 11.18.
3
.1.3. 4-(3-Phenylureido)-N-(7-(trifluoromethyl)quinolin-4-yl)benzenesulfonamide 17
A mixture of 16 (3.67 g, 0.01 mol.) and phenyl isocyanate (1.21 g, 0.01 mol.) in dry DMF (30
mL) was heated under reflux for 12h. The reaction mixture was cooled and poured onto
ice/water. The obtained solid was crystallized from ethanol to give 17. Yellow powder, Yield
o
-1
8
1
8
1%, melting point >350 C, IR: ν /cm 3420, 3386, 3210 (NH), 1668 (C=O), 1625 (C=N),
max
1
389, 1155 (SO ). H-NMR (DMSO-d D O) δ: 6.7, 8.6 (2d, 2H, 2CH quinoline, J=7.5 Hz), 7.0-
2
6
2
1
3
.3 (m, 13 H, Ar-H + SO NH), 8.8 (s, 2H, 2NHCO, D O exchangeable). C-NMR (DMSO-d )
2
2
6
δ: 118.0, 120.2, 121.7 (2), 122.3 (2), 123.0, 124.5, 125.2, 126.9, 128.7(2), 129.7, 131.9 (2),
1
35.7, 138.0, 139.3, 141.4, 142.8, 149.7, 152.2, 152.5. Anal. Calcd. for C H F N O S (486.47):
23 17 3 4 3
C, 56.79; H, 3.52; N, 11.52. Found: C, 56.98; H, 3.77; N, 11.21.
3
.1.4. 4-Isothiocyanato- 7-(triflouromethyl) quinoline 18
A mixture of 1 (2.31 g, 0.01 mol.) and ammonium thiocyanate (1.52 g, 0.02 mol.) in dry acetone
30 mL) was refluxed for 1h. The reaction mixture was cooled, poured onto ice/ water and the
obtained solid was crystallized from dioxane to give 18.Yellow crystals, Yield 96%, melting
(
o
-1
1
point 79.4 C, IR: ν /cm 3100 (CH arom.), 2059 (N=C=S), 1600 (C=N). H-NMR (DMSO-d
max
6
1
3
D O) δ: 7.8, 9.1 (2d, 2H, 2CH quinoline, J=7.8 Hz), 7.1-8.3 (m, 3 H, Ar-H). C-NMR (DMSO-
2
d6) δ: 120.6, 121.7, 124.1, 126.2, 126.8, 129.8, 130.1, 135.4, 137.6, 147.1, 152.6. Anal. Calcd.
for C H F N S (254.23): C, 51.97; H, 1.98; N, 11.02. Found: C, 51.68; H, 2.22; N, 11.31.
1
1
5
3
2
3
.1.5 General procedure for the synthesis of carbamimidothoic acid derivatives 19- 30.
A mixture of 18 (0.43 g, 0.001 mol.) and the appropriate sulfa drugs (0.0012 mol.) in dry DMF
30 mL) containing a catalytic amount of triethylamine was heated under reflux for 24h. The
obtained solid was filtered and crystallized from dioxane to give 19- 30, respectively.
(
3
.1.5.1.(E)-N-(4-sulfamoylphenyl)-N'-(7-(trifluoromethyl)quinolin-4-yl)carbamimidothioic acid
1
9
1
3

ACCEPTED MANUSCRIPT
o
-1
Brown powder, Yield 76%, melting point >350 C, IR: νmax/cm 3489, 3414, 3320 (NH, NH ),
2
1
1
6
625 (C=N), 1381, 1128 (SO ). H-NMR (DMSO-d D O) δ: 2.5 (s, 1H, SH, D O exchangeable),
2
6
2
2
.6, 8.5 (2d, 2H, 2CH quinoline, J=7.3 Hz), 6.8- 8.4 (m, 9H, Ar-H + SO NH ), 9.1 (s, 1H, NH,
2
2
1
3
D O exchangeable) C-NMR (DMSO-d ) δ: 116.9(2), 117.7, 122.9, 123.0, 123.6, 127.9(2),
2
6
1
28.3, 129.0, 129.3, 132.7, 143.0, 146.9, 153.0, 154.6, 164.2. Anal. Calcd. for C H F N O S
17 13 3 4 2 2
(426.44): C, 47.88; H, 3.07; N, 13.14. Found: C, 47.56; H, 3.28; N, 13.45.
3
.1.5.2. (E)-N-(4-(N-acetylsulfamoyl)phenyl)-N'-(7-(trifluoromethyl)quinolin-4-
yl)carbamimidothioic acid 20
o
-1
Brown powder, Yield 71%, melting point >350 C, IR: νmax/cm 3489, 3400 (NH), 1685 (C=O),
1
1
616 (C=N), 1327, 1114 (SO ). H-NMR (DMSO-d D O) δ: 2.4 (s, 3H, COCH ), 2.6 (s, 1H, SH,
2
6
2
3
D O exchangeable), 6.7, 8.9 (2d, 2H, 2CH quinoline, J=7.1 Hz), 7.5-8.4 (m, 8 H, Ar-H +
2
1
3
SO NH), 11.7 (s, 1H, NH, D O exchangeable). C-NMR (DMSO-d ) δ: 19.8, 113.7(2), 117.6,
2
2
6
1
23.7, 125.8(2), 127.6(2), 127.8, 128.0, 128.8, 132.0, 143.2, 148.7, 153.7, 155.9, 168.7, 188.2.
Anal. Calcd. for C H F N O S (468.47): C, 48.71; H, 3.23; N, 11.96. Found: C, 48.45; H,
1
9
15
3
4
3 2
3
.50; N, 11.66.
3
.1.5.3. (E)-N-(4-(N-carbamimidoylsulfamoyl)phenyl)-N'-(7-(trifluoromethyl)quinolin-4-
yl)carbamimidothioic acid 21
o
-1
Brown powder, Yield 81%, melting point 332.8 C, IR: νmax/cm 3429, 3373, 3330, 3221 (NH,
1
NH ), 1627 (C=N), 1398, 1130 (SO ). H-NMR (DMSO-d D O) δ: 2.5 (s, 1H, SH, D O
2
2
6
2
2
exchangeable), 5.6 (s, 2H, NH , D O exchangeable), 6.5, 8.8 (2d, 2H, 2CH quinoline, J=7.4
2
2
Hz), 6.7-7.9 (m, 8 H, Ar-H + SO NH), 8.2 (s, 1H, NH imino, D O exchangeable), 10.5 (s, 1H,
2
2
1
3
NH, D O exchangeable). C-NMR (DMSO-d ) δ: 112.2(2), 116.6, 118.5, 126.7(2), 127.2 (2),
2
6
1
27.4, 130.7(2), 139.1, 140.4, 151.3, 157.7, 158.0, 160.0 (2). Anal. Calcd. for C H F N O S
18 15 3 6 2 2
(468.48): C, 46.15; H, 3.23; N, 17.94. Found: C, 46.44; H, 3.52; N, 17.69.
3
.1.5.4. (E)-N-(4-(N-(3-methylisoxazol-5-yl)sulfamoyl)phenyl)-N'-(7-(trifluoromethyl)quinolin-4-
yl)carbamimidothioic acid 22
1
4

ACCEPTED MANUSCRIPT
o
-1
Brown powder, Yield 72%, melting point >350 C, IR: ν /cm 3487, 3406 (NH), 1620 (C=N),
max
1
1
381, 1138 (SO ). H-NMR (DMSO-d D O) δ: 2.3 (s, 3H, CH ), 2.6 (s, 1H, SH, D O
2
6
2
3
2
exchangeable), 6.0 (s, 1H, CH isoxazole), 6.6, 8.9 (2d, 2H, 2CH quinoline, J=7.0 Hz), 7.4-8.4
1
3
(
m, 8 H, Ar-H + SO NH), 9.1 (s, 1H, NH, D O exchangeable). C-NMR (DMSO-d ) δ: 18.2,
2 2 6
1
00.7, 116.6 (2), 117.8, 122.3, 124.0, 124.9, 128.6 (2), 128.7, 129.8, 132.0, 132.9, 142.8, 143.7,
52.6, 155.8, 160.0, 161.8, 162.1. Anal. Calcd. for C H F N O S (507.51): C, 49.70; H, 3.18;
1
2
1
16
3
5
3 2
N, 13.80. Found: C, 49.39; H, 3.38; N, 13.46.
3
.1.5.5. (E)-N-(4-(N-(3,4-dimethylisoxazol-5-yl)sulfamoyl)phenyl)-N'-(7-
(trifluoromethyl)quinolin-4-yl)carbamimidothioic acid 23
o
-1
Brown powder, Yield 82%, melting point >350 C, IR: ν /cm 3491, 3404 (NH), 1620 (C=N),
max
1
1
381, 1138 (SO ). H-NMR (DMSO-d D O) δ: 2.4 (s, 6H, 2CH ), 2.6 (s, 1H, SH, D O
2
6
2
3
2
exchangeable), 6.5, 8.5 (2d, 2H, 2CH quinoline, J=7.2 Hz), 6.9-8.3 (m, 8H, Ar-H + SO NH), 9.0
2
1
3
(
s, 1H, NH, D O exchangeable). C-NMR (DMSO-d ) δ: 9.9, 16.2, 101.2, 115.7(2), 118.6,
2
6
1
1
5
21.3, 124.0, 125.6, 128.7(2), 128.9, 129.2, 129.8, 132.5, 142.8, 144.9, 153.6, 156.0, 156.7,
58.2, 163.1. Anal. Calcd. for C H F N O S (521.54): C, 50.66; H, 3.48; N, 13.43. Found: C,
2
2
18
3
5
3 2
0.31; H, 3.19; N, 13.71.
3
.1.5.6. (E)-N-(4-(N-thiazol-2-ylsulfamoyl)phenyl)-N'-(7-(trifluoromethyl)quinolin-4-
yl)carbamimido-thioic acid 24
o
-1
Brown powder, Yield 78%, melting point >350 C, IR: ν /cm 3404, 3329 (NH), 3100 (CH
max
1
arom.), 1614 (C=N), 1379, 1130 (SO ). H-NMR (DMSO-d D O) δ: 2.6 (s, 1H, SH, D O
2
6
2
2
exchangeable), 6.7, 8.5 (2d, 2H, 2CH quinoline, J=6.8 Hz), 7.1-8.4 (m, 10H, Ar-H + SO NH),
2
1
3
1
0.6 (s, 1H, NH, D O exchangeable). C-NMR (DMSO-d ) δ: 116.0 (2), 116.3, 119.4, 119.9,
2 6
1
22.4, 125.1, 128.6 (2), 128.9, 129.0, 129.8, 133.1, 143.6, 146.2, 146.8, 152.6, 153.9, 155.0,
62.2. Anal. Calcd. for C H F N O S (509.55): C, 47.14; H, 2.77; N, 13.74. Found: C, 47.49;
1
20
14
3
5
2 3
H, 2.41; N, 13.98.
3
.1.5.7. (E)-N-(4-(N-pyridin-2-ylsulfamoyl)phenyl)-N'-(7-(trifluoromethyl)quinolin-4-
yl)carbamimido-thioic acid 25
1
5

ACCEPTED MANUSCRIPT
o
-1
Brown powder, Yield 81%, melting point >350 C, IR: ν /cm 3362, 3278 (NH), 3079 (CH
max
1
arom.), 1627 (C=N), 1381, 1158 (SO ). H-NMR (DMSO-d D O) δ: 2.6 (s, 1H, SH, D O
2
6
2
2
exchangeable), 6.7, 8.5 (2d, 2H, 2CH quinoline, J=6.8 Hz), 7.5-8.4 (m, 12H, Ar-H + SO NH),
2
1
3
9
.9 (s, 1H, NH, D O exchangeable). C-NMR (DMSO-d ) δ: 108.9, 112.8, 117.2 (2), 118.0,
2 6
1
22.6, 124.4, 125.1, 128.7(2), 128.9, 129.2, 129.9, 131.0, 136.7, 145.8, 148.6, 151.6, 152.1,
53.4, 158.2, 162.2 . Anal. Calcd. for C H F N O S (503.52): C, 52.48; H, 3.20; N, 13.91.
1
2
2
16
3
5
2 2
Found: C, 52.77; H, 3.02; N, 13.59.
3
.1.5.8. (E)-N-(4-(N-pyrimidin-2-ylsulfamoyl)phenyl)-N'-(7-(trifluoromethyl)quinolin-4-
yl)carba-mimidothioic acid 26
o
-1
Brown powder, Yield 69%, melting point 194.7 C, IR: ν /cm 3427, 3360 (NH), 3068 (CH
max
1
arom.), 1581 (C=N), 1325, 1155 (SO ). H-NMR (DMSO-d D O) δ: 2.7 (s, 1H, SH, D O
2
6
2
2
exchangeable), 6.5, 8.5 (2d, 2H, 2CH quinoline, J=6.9 Hz), 7.0-8.5 (m, 11H, Ar-H + SO NH),
2
1
3
1
1.4 (s, 1H, NH, D O exchangeable). C-NMR (DMSO-d ) δ: 112.1, 116.4 (2), 118.5, 121.4,
2 6
1
24.7, 126.1, 128.9 (2), 129.0, 129.3, 129.7, 134.4, 142.0, 142.8, 153.0, 157.1, 158.2 (2), 162.3,
62.6. Anal. Calcd. for C H F N O S (504.51): C, 49.99; H, 3.00; N, 16.66. Found: C, 49.68;
1
21
15
3
6
2 2
H, 2.79; N, 16.96.
3
4
.1.5.9. ((E)-N-(4-(N-(4-methylpyrimidin-2-yl)sulfamoyl)phenyl)-N'-(7-(trifluoromethyl)quinolin-
-yl)carbamimidothioic acid 27
o
-1
Brown powder, Yield 65%, melting point 256.9 C, IR: ν /cm 3379, 3251 (NH), 3093 (CH
max
1
arom.), 2934, 2861(CH aliph.), 1631 (C=N), 1381, 1151 (SO ). H-NMR (DMSO-d D O) δ: 2.1
2
6
2
(
s, 3H, CH ), 2.7 (s, 1H, SH, D O exchangeable), 6.5, 8.6 (2d, 2H, 2CH quinoline, J=7.0 Hz),
3 2
1
3
7
.1-8.6 (m, 10H, Ar-H + SO NH), 10.7 (s, 1H, NH, D O exchangeable). C-NMR (DMSO-d )
2 2 6
δ: 23.4, 109.2, 115.6(2), 117.6, 120.6, 124.0, 124.6, 128.1(2), 128.4, 128.6, 129.3, 129.5, 141.1,
1
5
51.1, 151.8, 157.0, 162.3, 163.7, 165.9, 166.6. Anal. Calcd. for C H F N O S (518.53): C,
22 17 3 6 2 2
0.96; H, 3.30; N, 16.21. Found: C, 51.26; H, 3.56; N, 16.03.
3
.1.5.10. (E)-N-(4-(N-(4,6-dimethylpyrimidin-2-yl)sulfamoyl)phenyl)-N'-(7-
(trifluoromethyl)quinolin-4-yl)carbamimidothioic acid 28
1
6

ACCEPTED MANUSCRIPT
o
-1
Brown powder, Yield 62%, melting point >350 C, IR: ν /cm 3367, 3242 (NH), 3082 (CH
max
1
arom.), 2931, 2860(CH aliph.), 1597 (C=N), 1379, 1151 (SO ). H-NMR (DMSO-d D O) δ: 2.2
2
6
2
(
s, 6H, 2CH ), 2.7 (s, 1H, SH, D O exchangeable), 6.0 (s, 1H, CH pyrimidine), 6.5, 8.4 (2d, 2H,
3 2
2
CH quinoline, J=7.1 Hz), 7.1-8.6 (m, 8H, Ar-H + SO NH), 10.6 (s, 1H, NH, D O
2 2
1
3
exchangeable). C-NMR (DMSO-d ) δ: 23.0(2), 103.7, 118.1(2), 118.5, 120.3, 124.5, 124.9,
6
1
26.0(2), 126.1, 129.0, 129.3, 130.2, 147.6, 151.7, 152.8, 156.6, 160.1, 162.2(2), 167.2. Anal.
Calcd. for C H F N O S (532.56): C, 51.87; H, 3.60; N, 15.78. Found: C, 51.51; H, 3.39; N,
2
3
19
3
6
2 2
1
5.43.
3
.1.5.11. (E)-N-(4-(N-(2,6-dimethoxypyrimidin-4-yl)sulfamoyl)phenyl)-N'-(7-
(trifluoromethyl)quinolin-4-yl)carbamimidothioic acid 29
o
-1
Brown powder, Yield 73%, melting point 331.3 C, IR: ν /cm 3350, 3234 (NH), 3100 (CH
max
1
arom.), 2953, 2846(CH aliph.), 1593 (C=N), 1381, 1145 (SO ). H-NMR (DMSO-d D O) δ: 2.6
2
6
2
(s, 1H, SH, D O exchangeable), 3.7, 3.8 (2s, 6H, 2OCH ), 5.9 (s, 1H, CH pyrimidine), 6.6, 8.6
2 3
(
2d, 2H, 2CH quinoline, J=7.0 Hz), 7.4-8.7 (m, 8H, Ar-H + SO NH), 10.9 (s, 1H, NH, D O
2
2
1
3
exchangeable). C-NMR (DMSO-d ) δ: 54.3, 54.8, 84.1, 116.7(2), 117.3, 122.5, 123.6, 124.1,
6
1
28.7(2), 128.8, 129.1, 129.3, 135.6, 150.5, 151.3, 156.8, 158.1, 160.1, 164.3, 171.5, 173.2.
Anal. Calcd. for C H F N O S (564.56): C, 48.93; H, 3.39; N, 14.89. Found: C, 48.59; H,
2
3
19
3
6
4 2
3
.12; N, 14.60.
3
.1.5.12. (E)-N-(4-(N-(5,6-dimethoxypyrimidin-4-yl)sulfamoyl)phenyl)-N'-(7-
(trifluoromethyl)quinolin-4-yl)carbamimidothioic acid 30
o
-1
Brown powder, Yield 61%, melting point >350 C, IR: ν /cm 3442, 3380 (NH), 2978, 2871
max
1
(
CH aliph.), 1591 (C=N), 1379, 1151 (SO ). H-NMR (DMSO-d D O) δ: 2.7 (s, 1H, SH, D O
2
6
2
2
exchangeable), 3.8 (s, 6H, 2OCH ), 6.5, 8.6 (2d, 2H, 2CH quinoline, J=6.8 Hz), 7.0-8.5 (m, 9H,
3
1
3
Ar-H + SO NH], 8.7[s,1H, CH pyrimidine), 10.8 (s, 1H, NH, D O exchangeable). C-NMR
2
2
(
DMSO-d ) δ: 54.0(2), 117.7(2), 118.5, 122.1, 124.2, 125.9, 127.1(2), 127.2, 128.8, 129.7, 132.4,
6
1
32.7, 142.8, 150.5, 150.7, 153.0, 157.9, 160.2, 161.5, 167.1. Anal. Calcd. for C H F N O S
23 19 3 6 4 2
(564.56): C, 48.93; H, 3.39; N, 14.89. Found: C, 49.26; H, 3.64; N, 15.28.
1
7

ACCEPTED MANUSCRIPT
3
.2. Molecular docking
All the molecular modeling studies were carried out on an Intel Pentium 1.6 GHz processor, 512
MB memory with Windows XP operating system using Molecular Operating Environment
(MOE, 10.2008) software. All the minimizations were performed with MOE until a RMSD
-1
o-1
gradient of 0.05 kcal mol A with MMFF94X force field and the partial charges were
automatically calculated. The X-ray crystallographic structure of franesyltransferase and arginine
methyltransferase (PRMT1) complexes with their ligands (PDB ID: 3E30, 3Q7E) were obtained
from the protein data bank. The enzymes were prepared for docking studies where: (i) Ligand
molecule was removed from the enzyme active site. (ii) Hydrogen atoms were added to the
structure with their standard geometry. (iii) MOE Alpha Site Finder was used for the active sites
search in the enzyme structure and dummy atoms were created from the obtained alpha spheres.
(iv) The obtained model was then used in predicting the ligand enzymes interactions at the active
site
3
.3. In vitro antitumor activity
The cytotoxic activity was measured in vitro for the newly synthesized compounds using the
Sulfo-Rhodamine-B stain (SRB) assay using the method of Skehan et al. [40]. The in vitro
anticancer screening was done by the pharmacology unit at Pharmacognosy Department, College
of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
Cells were plated in 96-multiwell plate (104 cells/well) for 24 h before treatment with the
compound(s) to allow attachment of cell to the wall of the plate. The tested compounds were
dissolved in dimethyl sulfoxide. Different concentrations of the compound under test (10, 25, 50,
and 100 µM) were added to the cell monolayer. Triplicate wells were prepared for each
o
individual concentration. Monolayer cells were incubated with the compound(s) for 48 h at 37 C
and in atmosphere of 5% CO . After 48 h, cells were fixed, washed and stained for 30 min with
2
0
.4% (wt/vol) SRB dissolved in 1% acetic acid. Excess unbound dye was removed by four
washes with 1% acetic acid and attached stain was recovered with Trise-EDTA buffer. Color
intensity was measured in an ELISA reader. The relation between surviving fraction and drug
concentration is plotted to get the survival curve for breast tumor cell line after the specified
1
8

ACCEPTED MANUSCRIPT
time. The molar concentration required for 50% inhibition of cell viability (IC ) was calculated
5
0
and compared to the reference drug Doxorubicin (CAS, 25316-40-9).
Acknowledgment
This study was supported by the National Plan for Science and Technology Program, King Saud
University (Grant 10-MED-1223-02), King Abdulaziz City for Science and Technology, Riyadh,
Saudi Arabia.
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Figure 1: X-ray crystallography of compound 2 with ethanol and methanol
Figure 2: Co-crystallized quinoline ligand on the active site of phosphoinisitol kinase
(PI3K)
Figure 3: Compound 29 on the active site of phosphoinisitol kinase (PI3K)
Figure 4: 3D interactions of compound 15 on the active site of PI3K enzyme
2
3

ACCEPTED MANUSCRIPT
Table 1
Binding scores and amino acid interactions of the docked compounds on the active site of
phosphoinisitol kinase (PI3K).
Compound
No.
S
Amino acid interactions
Interacting groups
N-quinoline
H bond
length
A
2.58
Kcal/Mol
o
2
3
-14.5528
-18.1977
Lys 890
Lys 833, Lys 890
N-quinoline,
NHCO
2.57, 2.46
4
5
6
7
8
9
-26.4252
-18.2927
-19.4952
-19.6350
-18.4821
-22.4510
Asp 841(water), His 957
Lys 833
N-quinoline, NH
NH
3.05, 2.48
2.78
Lys 833, Lys 890
Ser 836, Lys 808
SO
, N-quinoline
2.35, 2.64
2.79, 3.03
2
SO , N oxazole
2
Asp 841(water), Lys 867
Lys 808, His 848(water)
N-quinoline, SO
3.06, 2.60
3.29, 2.70
2
SO , N-isoxazole
2
Lys 890
N-quinoline
2.70
Asp 841(water), His 867
Lys 808, His 848
N-quinoline, SO
SO , N-thiazole
3.01, 2.04
2.70, 3.06
2
2
Asp 841(water), Lys 808
Asn 861, His 867
N-quinoline, SO
3.24, 2.07
3.06, 2.72
2
SO , N-pyridine
2
2
4

ACCEPTED MANUSCRIPT
1
1
0
1
-19.4511
-22.7769
Asn 861, Lys 833
N-pyrimidine, SO
2
2.90, 2.56
Lys 890, Lys 808
Lys 833, Ser 836
N-quinoline, SO
2.95, 3.15
2.83, 2.83
2
SO , NH
2
1
1
1
2
3
4
-23.1235
-25.7419
-18.0536
Asp 841 (water),
Lys 808, His 807
N-quinoline
3.01
SO , N-pyrimidine 2.58, 3.08
2
Asp 841 (water)
Lys 890, Lys 890
N-quinoline
3.12
SO , N-pyrimidine 3.10, 2.61
2
Lys 890
Ser 806
N-quinoline
N-pyrimidine
2.59
2.53
1
1
5
6
-23.7148
-18.2562
Lys 890, Lys 833
N-quinoline, SO
2
2.74, 2.77
Ser 836, Asp 841
Lys 833
SO
, NH
3.00, 1.34
2.33
2
SO2
1
7
-19.3946
Ser 836, Val 802
Val 802
N-quinoline, NH
C=O
2.82, 3.01
3.78, 3.60
1
2
2
2
2
2
9
0
1
2
3
4
-21.1616
-14.8902
-20.3150
-16.7515
-24.8105
-21.9811
Asp 841(water), Asp 864
Asp 841(water), Asp 954
Lys 833, Glu 889
N-quinoline, NH
2.93,1.31
2.41, 2.60
2.87, 2.41
2.44, 2.96
2.76, 2.40
3.05, 2.74
SO
N-quinoline, NH
, C=O
2
Ser 836, Lys 833
SO2, SO
SO2, SO
2
Ser 836, Lys 833
2
Ser 836, Lys 890
N-quinoline, N-
thiazole
2
2
2
2
5
6
7
8
-22.1491
-20.1491
-22.3484
-22.4054
Ser 836, Lys 890
Lys 890
SO2, SO
2
3.03, 2.66
2.95
N-quinoline
Lys 890, Lys 890
N-pyrimidine, SO
2.77, 2.40
2
Lys 890, Ser 808
Lys 833, Asp 864
N-quinoline, SO
2.74, 2.89
2.37, 1.39
2
SO , NH
2
2
9
-27.2076
Lys 808, Lys 890
Asp 841(water)
N-quinoline, C=N
N-pyrimidine
2.65, 2.92
3.08
2
5

ACCEPTED MANUSCRIPT
3
0
-19.0437
Asp 841(water), Lys 833
Lys 890
N-quinoline, C=N
SO2
2.46, 2.66
3.24
Table 2
In vitro anticancer screening of the synthesized compounds against six cell lines
Compound
No.
MDA-
MB231
HT 1080
(skin
HepG2 (liver
cancer cells) (colorectal Raw
Lovo
AS49- Hela
cells
(
breast
cancer
cells)
cancer
cells)
(lung
cancer
cells)
cancer
cells)
IC (µM)
5
0
2
3
4
5
6
7
8
9
34.40
56.06
41.55
49.81
33.55
31.88
25.81
40.34
41.80
27.16
32.50
32.77
39.19
25.96
17.89
29.57
25.44
31.02
28.32
24.29
27.34
27.74
27.31
50.76
45.99
NA
33.55
40.80
82.60
NA
46.10
NA
NA
26.56 79.01 61.17
51.47 64.18 NA
24.65 55.25 41.26
33.56 74.76 97.59
75.58
28.83
74.76
39.31
52.82
90.78
18.40
54.73
NA
36.02 53.08
NA
56.77 52.82 34.10
NA 66.08 70.75
20.22 30.38 44.76
27.41 34.23 78.06
1
1
1
1
1
1
1
1
1
2
2
2
2
2
0
1
2
3
4
5
6
7
9
0
1
2
3
4
NA 62.52
44.33 NA 32.01
50.41 37.91 83.23
39.85 36.86 NA
NA
36.18
NA
NA
83.82
66.06
27.62
93.11
NA
52.17
28.41
33.48
28.49
36.76
28.16
49.41
18.39
30.95
52.93
52.87
58.64
NA
80.26
27.94
24.39
19.65 18.42 35.29
53.65 29.23 45.98
30.23 24.50 40.96
34.53 36.55 36.55
30.03 37.60 37.60
23.91 23.91 23.91
NA 60.16 60.16
67.05 34.01
NA
67.08 27.15 95.18
2
6

ACCEPTED MANUSCRIPT
2
2
2
2
2
3
5
6
7
8
9
0
49.30
45.16
29.78
52.91
52.09
82.99
33.98
28.04
29.12
28.67
29.48
29.48
22.76
19.22
28.04
42.08
NA
72.15
76.66
77.25
27.11
87.50 33.51 68.78
34.72 37.75 NA
31.03 31.03 31.03
40.21 43.41 32.98
76.65 64.45 53.79
28.39 81.76
NA
Doxorubicin
24.33 32.78 30.21
Figure 1: X-ray crystallography of compound 2 with ethanol and methanol
2
7

ACCEPTED MANUSCRIPT
Figure 2: Co-crystallized quinoline ligand on the active site of phosphoinisitol kinase (PI3K)
2
8