"Synthesis, Reaction and Antitumor Screening of Some New
Quinoline Derivatives.
Mohamed M. Ismail1, Saber E.S. Barakat2, Ashraf H. Bayomi3, Helmy M. Sakr2 and
Kamla M. A. El-Gamal3
1
Department of Organic Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
2
Department of Pharmaceutical Chemistry, Faculty of Pharmacy(Boys), Al-Azhar
University,Cairo, Egypt.
3
Department of
Organic Chemistry, Faculty of Pharmacy(Boys), Al-Azhar University,
Cairo, Egypt.
Abstract
Vilsmeier formulation of acetanilide I followed by treatment with hydroxyl amine produced
2-chloroquinoline-3-carbonitrile II that was condenced with thiourea
yielded 2-
mercaptoquinoline-3-carbonitrile III which was converted to its potassium salt VI. That was
reacted with methyl chloroacetate produce 2-substituted thioquinoline-3-carbonitrile that
when reacted with hydrazinehydrate yielded 2-93-cyanoquinoline-2-ylthio)acetohydrazide VI
that was reacted with carbondisulfide in presence potassium hydroxide with was converted to
the potassium salt of 2- ((5-mercatpto-1,3,4-oxadiazol-2yl)methyl)sulfanyl) quinoline-3carboxamid VIII. Treatment of VI with benzoyl chloride gave IX. Reaction of VI with
different aldehydes resulted in the corresponding imines XII. And reaction of VI with ethyl
iso thiocyanate and treatment of the resulted compound with sulfuric acid gave XI, treatment
of VI with acetylacetone, ethylacetoacetate and isatine produce XIII, IVX and XV
respectively. Some of the synthesized compound were screened for antitumor activity and that
was found the screened compound has not any antitumor activity.
Introduction
The biological importance of variety of quinolines and substituted quinolines has resulted in
much interest in their synthesis(1-6). As a continuation of our work on the synthesis of
heterocycles containing the quinoline moiety(7). The present work is aimed at synthesizing 2(3-cyanoquinoline-2-ylthio)acetohydrazide VI which is the building block from which many
derivatives VII to VX couled be obtained as shown in scheme (1) with the aim to screening
the synthesized compound to evaluate antitumor activity.
1
Experimental
All melting points were carried on Gallen Kamp point apparatus and are uncorrected. The
infrared spectra were recorded on Brucker- Vector-22-F T-IR spectrophotometer using the
potassium bromide disc technique. The 1HNMR spectra were recorded or varian-Gemini300-MHz spectrophotometer using CDCl3 or DMSO-d6 as a solvents and TMS as internal
reference. The chemical shift value were recorded in  ppm downfield the TMS signal. The
Mass spectra were recorded on AZH-ph-AR-XO2 Mass spectrometer. Elemental analyses
were performed on CHN analyzer. All spectral measurements have been performed at the
Micro analytical Center, Cairo University, Egypt.
Following reported procedures, 2-chloroquinoline-3-carbonitrile II(4) 2-mercapto quinoline-3carbonitrile(5) and it’s salt(6) and 2-(methyl oxo carbonyl methyl thio) quinoline-3-carbanitrile
VII(6) were prepared.
Following reported procedures, 2-chloroquinoline-3-carbonitrile (II)(5) 2-mercapto quinoline3-carbonitrile(III)(6) and it’s salt (IV)(7) and 2-(methyloxycarbonyl-methyl thio)-quinoline-3carbonitrile(V)(7).
2-(3-Cyanoquinoline-2-yl-thio) acetohydrazide (VI)
To well stirred suspension of 3-cyanoquinoline-2-yl sulfonyl acetic acid methyl ester (2.58 g,
0.01 mol) in absolute ethanol (100 ml) hydrazine hydrate (80%) (10 ml) (0.01 mol) was
added. The reaction mixture was heated under reflux with stirring for three hours. The
precipitated solid was filtered off while hot, washed with absolute ethanol, dried at 200oC in
vacuum and crystallized from ethanol.
m.p.
>300
yield
90%
C12H10N4OS (258.35). Calc. (found C% 55.78 (55.67), H% 3.90 (3.56), N% 21.68 (22.00).
IV: 1HNMR: (DMSO, ppm): 9.04 (s,1H, H-4), 8.09-8.03(d,1H, H-5), 7.89-7.86 (d, 1H, H-8),
7.85-7.83(t,1H, H-6), 7.80-7.62(t,1H, H-7), 7.61 (s, 2H, S-CH2), 7.59-7.29 (broad , t,
.
.
1H,. NH-NH2), 4.52 (broad , d, 2H, NH-N H2)
Ms : (m/z, abound %) : 258(50.5, M), 259 (22.6, M+1), 228(16.7, M-N2H2), 227 (100,
N2H3), 199 (35, M-CH3N2O), 155 (39.7, C10H7N2),128(25.7, cyanoquinoline cation).
Potassium salt of N-(mercapto thio carbonyl) 2-(3-cyano-quinoline-2-ylthio)acetohydrazid (VII)
Carbon disulfide (1 ml, 0.03 mol) was added drop wise to an ice-cooled solution of
potassium hydroxide (0.56g, 0.002 mol) in absolute ethanol (10 ml) containing (VI) (2.58g,
0.01 mol). The mixture was diluted with absolute ethanol (10 ml) and stirred for fourteen
2
hours, dry ethyl ether was then added (10 ml) and the separated solid was filtered and washed
twice with ether (20 ml). The product which was obtained in an almost quantitative yield was
used in the next reaction without further purification.
m.p.
> 300
yield
40%
C13H9N4OS3K (372.36).
2[((-5-Mercapto-1,3,4-oxadiazol-2-yl)methyl)sulfanyl]quinoline-3-carboxamide
potassium salt (VIII).
Method A
A compound (XV) (3.72 g, 0.01 mol) containing in (50 ml) absolute ethanol was refluxed for
five hours in 2N potassium hydroxide (10 ml). The reaction mixture was diluted with
absolute ethanol, (10 ml) then leave to cooled the separated solid was filtered, washed with
dry diethyl ether (100 ml) and crystallized from absolute ethanol.
Method B
The hydrazide (VI) (2.58 g, 0.01 mol), absolute ethanol (10 ml) and potassium hydroxide
(0.56g, 0.002 mol) was stirred for one hour until clear solution was obtained, carbon disulfide
(0.56 g, 0.002 mol) was added drop wise to the reaction mixture for 20 minutes with stirring.
The reaction mixture was then refluxed for five hours until all hydrogen sulfide has been
evolved, after evaporation of the solvent, the separated solid diluted with ethanol, leave for
five hours, filter the separated solid was filtered off, , washed with diethyl ether (100 ml) and
crystallized from absolute ethanol.
m.p.
> 300oC
yield
25 %
C13H9N4O2S2K, (356.23), Calc. (Found) : C% 43.82 (43.90), H% 2.54(2.50), N% 15.72
(15.70).
IR : (KBr, cm-1): 3421.5 (broad, S, NH2), 2924 (s, C-H, aromatic), 1676.8 (s, C=O).
Ms : (m/z, abound %) : 356 (21.8, M+), 357 (17.7, M+1), 286 (24.8, M-SK+H), 285 (100, MSK), 270 (20.3, M-SK-NH), 269 (31.2, M-NH2SK), 268(28.9, M-SKNH3), 160(29.7,
M-C3HN3O2SK), 154(32.7, C10H3NO).
2[(-5-Phenyl-1,3,4-oxadiazol-2-yl)methyl sulfanyl]quinoline-3carboxamide (IX).
A mixture of hydrazide (VI) (2.58 g, 0.01 mol) in glacial acetic acid (50 ml) and benzyl
chloride (1.4g, 0.01 mol) was refluxed for three hours, then the mixture was allowed to cool,
3
poured onto ice-cooled water with neutralization with acid with vigorous shaking. The
precipitated solid was filtered off, dried and recrystallized from ethanol.
m.p.
> 300 oC
yield
30 %
C19H14N4O2S, (362.38), Calc. (Found) : C% 62.96(63.00), H% 3.89(4.00), N% 15.46(15.80).
IR : (KBr, cm-1): 3400(b, NH2), 3058(s,C-H, aromatic), 2226(s, C N), 1702 (s,C=O), 16101536 (s, C=C, C=N aromatic).
Ms : (m/z, abound %) : 362(36.8, M), 227(95.9, C12H7N2OS), 226 (100, C12H6N2OS), 77
(25.3, C6H5), 153(13.7, carboquinoline cation)
N-(Ethyl amino thio carbonyl)-2-(quinoline-2-yl-thio-3-carbonitril)
acetohydrazide (X).
A mixture of hydrazide (VI) (2.58 g , 0.01 mol) and ethylisothiocyanate (8.7g, 0.01 mol) in
ethanol (10 ml) was heated under reflux for two hours, the separated solid was filtered off
and crystallized from ethanol.
m.p.
> 245 oC
yield
43 %
C15H15N5OS2, (345.43), Calc. (Found) : C% 52.15(52.40), H% 4.73(4.90), N% 20.27(20.53).
O
IR : (KBr, cm-1): 3351.8 (s, HN C ) ,3290(s,NH-CH3), 3101(s,C-H aromatic) 3043.1 (s,C-H
aliphatic), 2367.5 (s, C N), 1793(s,C=S), 1728 (s,C=O), 1610 -1522(s,C=C, C=N
aromatic).
2-[(-5-Ethyl amino)-1,3,4-thiadiazol-2-yl)methyl thio]quinoline-3-carbonitrile
(XI).
Compound (X) (3.45 g, 0.01 mol) was dissolved in conc. sulfuric acid ( 10 ml) while cooling
and allowed to stand for 15 minutes. The reaction mixture was then quenched with ice and
treated with conc. ammonia solution till neutral to litmus paper, the separated solid
crystallized from ethanol.
m.p.
218oC
yield
27%
C15H13N5S2 (327.41) Calc. (Found) : C% 55.02 (55.30), H% 4.00 (3.90), N% 21.39 (21.50).
IR (KBr, cm-1): 3420 (b, NH,Et), 3011.8 (s, C-H, aromatic), 2925 (s, C-H aliphatic) , 2227.5
(s, CN).
4
MS (m/z, abound %) : 327(2.5, M), 312 (4.8, M-CH3), 311(13.2, M-CH4), 258(38.9, MC3H5N2),
228(21.9,
M-C3H3N2S),
199
(36.4,
C11H7N2S),
153(11.7,
Cyanoquinoline cation), 128 (25.5, C9H6N).
Substituted 2-(3-cyanoquinoline-2-yl)-N-benzlidene aceto-hydrazide (XIIa-g)
To a will stirred suspension of 2-(3-cyanoquinoline-2-yl-thio)-acetohydrazide (VI)(2.5 g,
0.01 mol) in absolute ethanol (50 ml) containing few drops of acetic acid (98%). The
appropriate aromatic aldehyde (0.01 mol) was added and the mixture was then heated under
reflux for six hours, the reaction mixture was concentrated under reduced pressure, then
allowed to cool. The separated solid was filtered, dried and crystallized from absolute ethanol
(table 1)
Table
(1):
The
physical
data
and
elemental
analysis
of
subs-2-(3-
cyanoquinoline-2-yl-thio)-N-benzylidene acetohydrazide (XXa-g)
Comp.
No
C6H4Cl(2)
m.p.
(oC)
279-280
C6H3Cl2(2,4)
289-290
87
C6H3Cl2(2,6)
240-241
80
C6H4OCH3(4)
250-252
80
C6H4NO2(3)
295-297
60
C6H4NO2(4)
284-285
65
C6H2(OCH3)3(34,5)
260-262
85
R
Yield
90
a
b
d
d
e
f
g
Mol. Form.
(M.Wt.)
C19H13ClN4OS
380.83
C19H12Cl2N4OS
415.29
C19H12Cl2N4OS
415.29
C20H16N4O2S
376.42
C19H13N5O3S
391.39
C19H13N5O3S
391.39
C22H20N4O4S
436.7
Elemental analysis
C
H
N
59.91 3.43 14.17
60.53 3.40 14.66
54.94 2.91 13.49
54.27 3.36 13,85
54.94 2.91 13.49
54.27 3.36 13.96
63.81 4.28 14.88
63.12 4.07 15.10
58.30 3.09 17.89
58.57 3.24 18.00
58.30 3.09 17.89
58.41 3.38 17,90
60.53 4.61 12.83
60.53 4.56 12.26
XII-a: IR: (KBr, cm-1): 3420(s, NH), 3136(s,C-H aromatic) , 2944 (s,C-H, aliphatic), 2250 (s,
C N), 1694 (s, C=O), 1594 (s, C=C aromatic)
Ms (m/z, abound %): 380 (32.2, M), 382(14.2, M+2H), 381 (9.6, M+1), 22.8(11.8,
C12H8N2OS), 227 (100, C12H7N2OS), 199 (19.9, C11H7N2S), 172(10.7, C10H6NS).
O
XII-b: 1HNMR: (DMSO, ppm): 11.82 (s,1H,
.
C NH
), 9.23(s,1H-N=CH-), 8.47 (s,1H,
H-4), 8.24-8.20(d,2H, H-5,6 of phenyl ring), 8.11-8.06 (d,2H, H-5,H-8),7.917.85(t,1H, H-6), 7.75-7.72 (s,1H, H-3 of phenyl), 7.64-7.61(t,1H, H-7), 2.51 (s,2H,
S-CH2).
5
XII-c: IR: (KBr, cm-1): 3386(s, NH), 3290(s,C-H aromatic), 2942 (s, C-H, aliphatic),2290(s,
CN), 1700(s, C=O), 1596(s, C=C, aromatic).
XII-d: 1HNMR: (DMSO, ppm): 11.41(s,1H, NH), 9.17(s,1H, -N=CH), 8.01-8.09 (s,1H, H4), 8.08-8.6(d,1H, H-5), 7.88-7.86(d,1H, H-8), 7.86-7.83(t,1H, H-7), 7.83-7.77
(t,1H, H-6), 7.63-7.69(d,2H, H-3,5 of phenyl ring), 7.88-7.83(d,2H, H-2,6 of phenyl
.
ring), 3.83(s,2H, S-CH -CO), 3.32(s,3H, OCH ).
2
3
XII-e: IR: (KBr, cm-1): 3336(s, NH), 2932(s,C-H aromatic) , 2223 (s, C N), 1710 (s, C=O),
1585 (s, C=C aromatic)
XII-f: 1HNMR: (DMSO, ppm): 11.41 (s,1H, NH), 9.21(s,1H, N=CH), 8.40-8.37(d,2H, H3,5 of phenyl ring), 8.20(s,1H, H-4), 8.10-8.05(d,4H,H-5, H-8, H-2,6 of phenyl
ring), 7.89-7.84 (t,,1H, H-7), 7.66-761 (t,1H, H-6).
XII-g: IR: (KBr, cm-1): 3310(s, NH), 3090(s,C-H aromatic) , 2870 (s,C-H, aliphatic), 2222 (s,
C N), 1700 (s, C=O), 1586 (s, C=C aromatic)
2-((3-Methyl pyrazolo-1-yl-5-one)carbonylmethyl thio) quinoline-3-carbonitrile
(XIII).
To a suspension of the hydrazide (VI) (2.58g, 0.01 mol) in acetic acid (98%) or dry dioxan
(50 ml),ethyl acetoacetate (1.3g, 0.01 mol) was added and the reaction mixture was refluxed
for four hours and then allowed to cool. The separated solid was collected as very pure
crystals which was washed with ethanol.
m.p.
240oC
yield
30%
C16H11N4O2S (323.43), Calc. (Found), C% 59.42(59.57), H% 342 (3.50), N% 17.32(17.80)
1HNMR:
(DMSO, ppm): 9.17 (s,1H, H-4), 8.18-8.15(d,1H, H-5), 8.04-8.01(d,1H, H-8),
7.87-7.82 (t,1H, H-6), 7.65-7.63(t,1H, H-7),6.17(s,1H, H-4 of pyrazolone ring),
3.32(s,2H, S-CH2), 2.35(s, 3H, CH3 of pyrazolone ring).
MS: (m/z, abound %) : 324(60.3, M), 325(16.7, M+1), 283(19.1 ,M- C2H3N), 282(100, MC2H4N), 253 (30.2, C13H7N3OS), 153(14.7, cyanoquinoline cation)
2-((3,5-Methyl pyrazolo-1-yl)carbonylmethyl thio) quinoline-3-carbonitrile (IVX).
A mixture of 2-(3-cyanoquinoline-2-yl-thio)acetohydrazide (VI) (2.58g, 0.01 mol) in dry
dioxan (50 ml) and acetylacetone (1g, 0.01 mol) was heated under reflux for three hours with
stirring. The reaction mixture was allowed to cool, the separated solid was filtered off,
washed with hot absolute ethanol and collected as very pure yellow crystals.
6
m.p.
220oC
yield
50%
C17H14N4OS (322.37), Calc. (Found), C% 63.33(63.68), H% 4.37(4.60), N% 17.38(17.25)
1HNMR:
(CDCl3, ppm): 8.14(s,1H, H-4), 8.14-8.11(d.1H, H-5), 7.96-7.93(d,1H, H-8),
7.50-7.48(t,1H, H-6), 7.55-7.52 (t,1H, H-7), 6.02(s, 1H, H-4 of pyrazol), 2.66(s,2H,
.
S-CH2), 2.34(s, 3H, CH3 at position 5 of pyrazol),
1.56(s,3H, CH3 at position 3 of
pyrazol).
MS: (m/z, abound %) : 322(76.8, M), 323(17.6, M+1), 227(29.3 ,M- pyrazol ring), 226 (100,
C12H6N2OS)198 (52.6, C11H6N2S), 154 (33.2, C10H6N2), 153(9.0, cyanoquinoline
cation).
2-(3-cyanoquinoline-2-yl-thio)-N-(oxoindolin-3-ylidene)aceto-hydrazide(VX)
To a solution of 2-(3-cyanoquinoline-2-yl-thio)-N-(oxoindolin-3-ylidene) aceto-hydrazide
(2.58g, 0.01 mol) in dry dimethyl formamide (10 ml) isatin (1.47g, 0.01 mol) was added and
the mixture was heated under reflux for four hours then allowed to cool, poured onto crushed
ice, the product was filtered off and crystallized from ethanol.
m.p.
276-278oC
yield
40%
C20H13N5O2S (387.43), Calc. (Found), C% 62.00(59.57), H% 3.38 (3.50), N% 18.07(17.80)
IR: (KBr, cm-1): 3426.8( S, NH), 3318.3(s,NH-N) , ,3652(s, C-H aromatic), 2925(s, C-H,
aliphatic), 2371.1(s,CN), 1696.8(s, C=O), 1617-1591.1(2,C=C, C=N aromatic).
MS: (m/z, abound %) : 387(38.5, M), 388(23.1, M+1), 270(14.3 ,C13H10N4OS), 269(44.7,
C13H9N=OS), 226(24.5, C12H6N2OS), 227(100, C12H7N2OS), 200(41.0, C11H8N2S),
199(81.1,
C11H7N2S),
198(23.4,
C11H6N2S),
154(27.8,
C10H6N2),
153(16.1
cyanoquinoline cation)
Antitumor screening of the (E.A.C)(8).
A set of sterile test used 2.5 x 105 tumor cells per ml were suspended in phosphate buffer
saline, then 25,50,100 µg / ml from nine compounds (VIII, IX, XI, XIIb, XIIg, XIII, IVX,
XV) were added to the suspension, kept at 37oC for 2 hours. Trypan blue dye exclusion test
was then carried out to calculate the per centage of non viable cells, it was found that the test
compound displayed no inhibitory activity against the experimental system tested.
Results and Discussion
2-chloroquinoline-3-carbonitrile (II) was prepared by one-pot reaction via vilsmeier
formulation of acetanilide (I) using (DMF/POCl3)(9-11) followed by treating with
hydroxylamine hydrochloride where by 44% yield of (II) was obtained 2-chloroquinoline-37
carbonitrile (II) was treated with thiourea in the presence of sodium hydroxide to give 2mercapto-3-carbonitrile (III)(6) which was treated with potassium hydroxide in absolute
ethanol to give the corresponding potassium salt (IV)(7) that was condensed with methyl
chloroactate to afforded (V)(7). Reaction of (V) with hydrazine hydrate ethanol 95% to give
the corresponding 2-(3-cyanoquinoline-2-ylthio) acetohydrazide (VI) the structure of (VI)
was confirmed by elemental and spectral data. The 1HNMR spectra of compound (VI)
characterized by triplet of one proton at 7.49-7.29 ppm that dispeared on equilibration with
D2O (due to NH). Douplet of two protons at 4.52 ppm that disappeared on equilibration with
-+
D2O (due to NH2) in addition to preence of singlet of two protons at 7.61 ppm ( S-CH2). The
El-Mass spectra of compound (VI) shows prominent molecular ion peak and the
fragmentation pattern are characterized by loss of NH-NH2 to produce the base peak. The
new derivatives of quinoline was obtained when (VII) was treated with potassium hydroxide
and carbon disulfide at room temperature to get the compound (VII) which was refluxed to
get the compound (VIII). The structure of (VIII) was confirmed by elemental analysis and
spectral data. The El-Mass spectra of compound (VIII) shows prominent molecular ion peak
and the fragmentation pattern are characterized by loss of SK to produce the base peak. The
attendens was extended to cyclize the hydrazide (VI) by reaction with benzoyl chlorie to
produce (IX) which confirmed by elemental and spectral data. The El-Mass spectra of
compound (IX) are characterized by distinct molecular ion peak, which on loss of phenyl
ring will produce the base peak. Moreover 2-(3-cyanoquinoline-2-ylthio) acetohydrazide (VI)
was allowed to react with ethyl isothiocyanate to get the compound (XI) while the reaction
procedure through two steps, the first step was proceed and get the compound with open
structure (X) which is different in melting point from. The start and the IR spectra was
characterized by absence of band at 3310.8 cm-1 (that due to NH2). The second step
containing the neutralization of (X) with concentrated sulfuric acid at room temperature will
afforded the compound (XI), the structure of (XI) was confirmed by elemental and spectral
data where the El-mass showing prominent molecular ion peak and the fragmentation pattern
might represent the base peak, loss of CN, NH-NH2CH3 from the molecular ion was
observed. Furthermore 2-(3-cyanquinoline-2-ylthio) acetohydrazied (VI) was allowed to
condense with different aromatic aldehydes where by some new Schiff’s bases (XII) were
obtained. The structures of compounds (XII) were confirmed by elemental and spectral data.
The 1HNMR spectra of compound (XIII) revealed a downfield singlet of one proton at about
11.41 ppm, disappeared on equilibration with D2O (-NH), a singlet of one proton at 9.17 ppm
(N=CH). The chractristic pattern of quinoline protons appeared in the region of 7.95-7.09
8
ppm. The El Mass spectra of compound (XII) are characterized by distinct molecular ion
peaks. The spectra are characterized by the presence of common peaks at m/z 22.7 which
represent the base peak (due to cleavage of the amide bond), 199 (due to loss of carbonyl
group from the pevious moiety). The present weak shows reaction of 2-(3-cyanoquinoline-2ylthio) acetohydrazide (VI) with two active methelene compounds the first is the
acetylacetone to produce the compound (XIII). The structure of compound (XIII) was
confirmed by elemental and spectral data. Appoint of interest was observed in 1HNMR
spectra which shows, two upper field singlet each of three protons at 2.50-2.35 ppm
indicating the presence of two different CH3 group of α--unsaturated ketone system in
addition a singlet of two protons at 3.32 ppm due to methylene protons and the spectrum
reveals a characteristic pattern displayed by quinoline protons. The El-mass are characterized
by very distinict molecular ion peak which is the base peak. The second is the
ethylacetoacetate to get the compound (IVX). The structure of compound (IVX) was
confirmed by elemental and spectral data. The 1HNMR spectra singlet which attributed to
two sligntly different CH3 group that was at 2.34 ppm(CH3 at position-5 of pyrazol) and at
1.56 ppm (at position-3 of pyrazol). In addition presence of singlet of two protons at 2.66
ppm (-S-CH2). The El spectra was characterized by presence of very distinct molecular ion
peak and loss pyrazol moiety will produce the base peak. Lastly the reaction of compound
(VI) with isatin afforded 2-(3-cyanoquinoline-2-yltio)-N-(oxo indolin-3-ylidene) acetohydrazied (VX) and the structure of compound ((VX) was confirmed by elemental and spectral
data. The IR spectra in KBr showed abroad band at 3426 cm-1
(-NH- stretching) and
sharp intense band at 2371 cm-1 (C N) and strong intense band at 1696 cm-1 (C=O). the Elmass spectrum of compound (VX) were characterized by presence of molecular ion peak
which due to brocken at amide bond will produce the base beak.
9
N
H
H2N
NH2OH.HCl
CH 3
O
CN
POCl3 l 80oC
O
N
CN
Cl
N
EtOH
SH
N
SK
IV
III
II
I
CN
KOH
NH 2
OCH3
Cl
O
CN
N
H
N
S
O
S
N
H
CN
CS2 /KOH

N
SK
H
N
S
CN
NH2-NH2-H2O
NH 2
N
OCH3
S
O
VI
O
V
O
VII
O
Cl
C NH
2
KOH / 
N N
G. Acetic acid
OH
N
S
IX

CS
2
/K
O
CN
NCS
N
O
N
H
O
NH 2
X
R.T
N
S
N N
S
O
SK
N
H
H2SO4
C
S
H
N
CN
VIII
N N
N
S
S
Cl
N
H
XI
O
CN
H
N
H
N
S
N
O
R
XII
R = C6H4Cl(2), C6H5Cl2(2,4), C6H5Cl2(2,6), C6H3OCH3(4)
R = C6H4NO2(3), C6H4NO2 (4), C6H2(OCH3)3(3,4,5)
O
O
N
N
S
N
O
CH 3
O
XIII
O
O
CN
O
CN
O
N
IVX
H
N
O
N
S
N
CN
H
N
O
N
S
VX
Scheme 1
10
CH 3
O
O
O
N
H
N
References
1) Coatney GR., Am, J. Trop med. Hyg., 12, 121 (1963).
2) Ridgway, M.h., Waters, M.D., Peel, E.M., Ellis, P.G., Ger offen 2, 407,
744 (1974); Chem. Abstr., 81, 169547s (1974).
3) Buckle D.R., Cantello, B.C.C., Smith, H., Spicer B.AS. , J. Med. Chem.,
18, 726 (1975).
4) Juergen, S., Jochen, W., Karl, R., Hubert, S., D.E., 3716512 (1988).
5) Bell, M.R. and Ackerman, J.H., U.S. pat. 4,920, 128 (1990).
6) Mekeimer, R., Ahmed, E., Kh, Khatab, A.F., Bull, Chem. Soc. Jpn. 66,
2936 (1993).
7) Monir, A.A., Mohammed, M.I., Saber, E.B., Ashraf, A.A. , Ashraf, H.B.
and Kamal, M.A.E., Bull Pharma. Sci, Assiut University, Vol. 27, part 2,
December, 2004 , pp. 237-245.
8) Melimans, W.F., Davis, E.V., Glover, F.L., and Rake, G.W., J. Jmmunol,
79, 428 (1957).
9) Meth-Chon, O., Narine, B. and Tarnowski, B., J. Chem. Soc., Perkin trans
I, 1520-1536 (1981) and Meth. Cohn, O., Rhouati, S., Tarnowsk, B. and
Robinson, A., ibid, 1537-1542 (1981).
10) Vilsmier, a. and Haack, A., Ber., 60B, 119 (1927).
11) Pizey, J.S., “Synthetic Reagents” Vol. 1,1-99 Wiley, New York (1974).
11
‫الملخص العربى‬
‫*محمد محسن اسماعيل ‪ **،‬صابر السيد بركات ‪ ***،‬أشرف حسن بيومى ‪** ،‬حلمى مصطفى صقر‪،‬‬
‫*** كمال محمد أحمد الجمل‬
‫*قسم الكيمياء العضوية ـ كلية الصيدلة ـ جامعة القاهرة‬
‫** قسم الكيمياء الصيدليه ـ كلية الصيدله(بنين) ـ جلمعة األزهر ـ القاهرة‬
‫*** قسم الكيمياء العضوية ـ كلية الصيدلة (بنين) ـ جامعة األزهر القاهرة‬
‫تم تفاعل فالسيماير على االسيتانيليد )‪ (I‬ثم معالجة الناتج بالهيدروكسييل أميين أعطيى ‪2‬ـي كليورو كينيولين‬
‫ـ‪3‬ـ كاربونيترييل )‪ (II‬واليى عنيد تفاعليه ميث الويويورييا أنيتج ‪2‬ـيمركابتوكينولين ـ‪3‬ـيكاربونتيريل )‪(III‬‬
‫والى تم تحويله الى الملح البوتاسيومى والى بتفاعليه ميث الميوييل كليورو أسييتات أعطيى الويوكينولينيات‬
‫المقابليية وبتفاعييل الهيييدرازين هيييدرات مييث )‪ (V‬أعطييى هيدرازيييدات الكينييولين الجديييدة )‪ (VI‬والتييى‬
‫بتفاعلها مث كاربون دا سيلفايد فيى وجيود هيدروكسييد البوتاسييو أعطيى المليح البوتاسييومى )‪(VIII‬‬
‫معالجة )‪ (VI‬ميث كلورييد البنيوييل أعطيى )‪ (IX‬وتفاعيل )‪ (VI‬ميث ييوييل زييوثيوسييانات ثيم معالجية‬
‫الناتج بحمض الكبريتك أنتج )‪ (XI‬تكاثف المركب )‪ (VI‬مث بعض األلدهيدات األرومانية أعطى بعض‬
‫اإلمينييات الجديييدة )‪ (IX‬معالجيية )‪ (IX‬مييث األسييتيل أسيييتون واإليويييل أسيتوأسيييتات واالزاتييين أنييتج‬
‫المركبييات )‪ (XV) ، (IVX) ، (XIII‬علييى التييوالى وقييد تييم أضتبييار بعييض المركبييات الجديييدة بيولوجيييا‬
‫كمضادات للسرطان حيث وجد أن كل المركبات التى أضتبرت ليست لها فاعلية‪.‬‬
‫‪12‬‬