Synthesis, antileishmanial and cytotoxicity activities of fused and nonfused tetrahydroquinoline derivatives

Article abstract of DOI:10.1007/s11164-018-3311-6

Developing novel antileishmanial, and cytotoxic drugs has been a significant area in modern pharmaceutical research. A series of novel triazolo[4,3-a]quinoline, triazino[4,3-a]quinoline, thiadiazepino[5,6-b]quinoline and pyrazolquinoline have been synthes

Full text of DOI:10.1007/s11164-018-3311-6

Res Chem Intermed
https://doi.org/10.1007/s11164-018-3311-6
Synthesis, antileishmanial and cytotoxicity activities
of fused and nonfused tetrahydroquinoline derivatives
Hassan Mohamed Fawzy Madkour1 ·
Maher Abd El‑Aziz Mahmoud El‑Hashash1 · Marwa Sayed Salem1 ·
Al‑Shimaa Omar Ali Mahmoud1
Received: 23 December 2017 / Accepted: 23 January 2018
© Springer Science+Business Media B.V., part of Springer Nature 2018
Abstract Developing novel antileishmanial, and cytotoxic drugs has been a sig-
nifcant area in modern pharmaceutical research. A series of novel triazolo[4,3-a]
quinoline, triazino[4,3-a]quinoline, thiadiazepino[5,6-b]quinoline and pyrazolqui-
noline have been synthesized from the reaction of 2-hydrazinyltetrahydroquinoline-
3-carbonitrile with formamide, formic acid, ethyl chloroacetate, carbon disulphide
in an alcoholic solution of potassium hydroxide acetyl acetone and/or ethyl cyanoac-
etate, respectively. These compounds were evaluated for their in vitro studies against
L. major leishmanial. The brine shrimp bioassay was also conducted to study their
in vitro cytotoxic properties which displayed potent cytotoxic activity against Vin-
1
cristine. The newly synthesized compounds were all characterized through IR, H-
NMR, and MS.
Keywords Tetrahydroquinolines · Triazolo[4,3-a]quinoline · Triazino[4,3-a]
quinoline · Thiadiazepino[5,6-b]quinoline · Antileishmanial · Cytotoxicity
Introduction
Tetrahydroquinolines are one of the important structural subunits of various natu-
rally occurring compounds and numerous recent reports have proved that com-
pounds containing the tetrahydroquinoline moiety elicit potent biological responses
leading to anti-infammatory [1], antinephritic [2], treatment of Alzheimer’s disease
[3], antitumor [4, 5] and antiallergenic [6] activities. In addition, many tetrahydro-
quinoline derivatives appeared as anti-HIV [7, 8], antimalarial [9, 10] cholesteryl
*
Marwa Sayed Salem
marwa_k@sci.asu.edu.eg
1
Synthetic Organic Chemistry Laboratory, Chemistry Department, Faculty of Science, Ain
Shams University, Abbassia, Cairo 11566, Egypt
1 3

H. M. F. Madkour et al.
ester transfer protein inhibitors [11], anti-diabetic [12, 13] and antioxidant [14]
agents. In recent years, the 5,6,7,8-tetrahydroquinolines have gained signifcant
attention due to their remarkable biological applications as tyrosine kinase inhibi-
tors, anticancer candidates [15] and cytotoxic activity against human colon carci-
noma HT29, hepatocellular carcinoma HepG2 and Caucasian breast adenocarci-
noma MCF7 cell lines [16].
In view of these points and related with our programme objectives of synthesis of
fused heterocyclic compounds and their biological evaluation, [17–23] the authors’
target, herein, it was thought worthwhile to study the synthesis of new heterocyclic
systems fused with the tetrahydroquinoline ring system in a single molecular frame-
work with the hope of getting agents of synergistic anticancer activity, lower toxicity
towards the normal cells, and antileishmanial activity.
Result and discussion
Chemistry
A facile one-pot four-components reaction was utilized to construct a mixture of
4-(4-methoxyphenyl)-2-oxo-1,2,3,4,5,6,7,8-octahydroquinoline-3-carbonitrile
(1)
and 4-(4-methoxyphenyl)-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonitrile (2),
via reaction of cyclohexanone, 4-methoxybenzaldehyde, ethyl cyanoacetate and
ammonium acetate in ethanol. Compound 1 has been confrmed via the isolation
of the same octahydroquinoline-3-carbonitrile 1 by the reaction of cyclohexanone,
4-methoxybenzaldehyde, cyanoacetamide and ammonium acetate in ethanol under
refux. It has been reported [24] that the reaction of cyclohexanone with the α,β-
unsaturated nitrile derivative in the presence of ammonium acetate in ethanol gave
the same products. Reaction of cyclohexanone, 4-methoxybenzaldehyde, malononi-
trile and ammonium acetate in ethanol under refux gave enaminonitrile 3. Chlorina-
tion of compound 2 with a mixture of phosphorous oxychloride and phosphorous
pentachloride gave the corresponding 2-chlorotetrahydroquinoline-3-carbonitrile 4
(cf. Scheme 1).
The reactivity of 2-chlorotetrahydroquinoline-3-carbonitrile 4 towards some
nucleophilic reagents such as sodium azide, thiosemicarbazide and hydrazine
hydrate in boiling ethanol has been investigated to give tetrahydrotetrazolo[1,5-a]
quinoline 5, bis compound 6 and 2-hydrazinyl-tetrahydroquinoline-3-carbonitrile 7,
respectively (cf. Scheme 2). The IR spectrum of compound 6 displayed absorption
bands at 3349, 2221 and 1250 cm−1 attributed to νNH, νC≡N and νC=S respectively; its
1H-NMR spectrum displays two singlet signals at 8.98 and 4.45 equivalent to a three
NH group. The IR spectrum of 7 displayed absorption bands at 3420, 3350 cm−1
due to asymmetry and symmetry of the NH2 group.
Compound 7 has been used in the synthesis of many novel biologically interest-
ing fused and nonfused heterocyclic ring systems. Consequently, 2-hydrazinoqui-
noline 7 when heated with formamide, and/or formic acid aforded triazolo[4,3-a]
quinoline derivatives 8 and 9, respectively. Triazino[4,3-a]quinoline 10 has been
synthesized by reacting 2-hydrazinoquinoline 7 with ethyl chloroacetate in pyridine
1 3

Synthesis, antileishmanial and cytotoxicity activities…
Ar
N
Ar
CN
O
CN
O
(i)
+
N
H
1
H
2
CHO
O
(iv)
(ii)
(1)
Ar
CN
Cl
Ar
N
OCH3
CN
N
4
(iii)
NH2
3
OCH3
Ar =
(i) CNCH2COOEt, AcONH4, EtOH; (ii) CNCH2CONH2, AcONH4, EtOH; (iii) CH2(CN)2, AcONH4, EtOH; (iv) POCl3,PCl5
Scheme 1 Synthesis of quinoline derivatives
Ar
CN
(i)
N
N
N
N
5
Ar
N
Ar
Ar
CN
N
CN
CN
Cl
S
(ii)
NH
NH NH
6
N
4
Ar
CN
(iii)
N
NHNH2
7
(i) NaN3,DMF/reflux; (ii) NH2NHCSNH2, EtOH, reflux; (iii) NH2NH2.H2O, EtOH, reflux
Scheme 2 Reactions of 2-chlorotetrahydroquinoline-3-carbonitrile 4 with diferent nitrogen nucleophiles
via a S2N reaction mechanism on the electron defcient CH2 group present between
the carbonyl group and chlorine atom of the ethyl chloroacetate followed by cycliza-
tion through attack of the imino group of the pyridone nucleus on the carbonyl of
ester group via the tetrahedral mechanism. However, reaction of 2-hydrazinoquino-
line 7 with carbon disulphide in an alcoholic solution of potassium hydroxide gave
thiadiazepino[5,6-b]quinoline derivative 11. According to our speculation, the latter
compound 11 was synthesized through nucleophilic attack of the amino group of the
2-hydrazinoquinoline 7 on the electron defcient C-atom of carbon disulfde and the
subsequent 1,3-proton shift and cyclization via attachment of the thiol functionality
1 3

H. M. F. Madkour et al.
on the cyano group through a SiN reaction mechanism. On the other hand, pyra-
zolquinoline derivatives 12 and 13 have been obtained via reaction of 2-hydrazino-
quinoline 7 with acetyl acetone and/or ethyl cyanoacetate in ethanol, respectively
(cf. Scheme 3).
The reactivity of the starting 2-hydrazinoquinoline 7 towards acetic anhy-
dride under all sets of conditions was investigated. The starting material 7 was
heated at refuxing temperature with acetic anhydride to aford N-acetyl-N′-[3-
cyano-4-(4-methoxyphenyl)-5,6,7,8-tetrahydroquinolin-2-yl]
acetohydrazide
(14). On the other hand, fusing of 2-hydrazinoquinoline 7 with acetic anhydride
gave an acetylated product then hydrolysis of a cyano group into carboxylic acid
Ar
CN
(i)
N
N
N
O
8
H
Ar
CN
(ii)
N
N
N
9
Ar
Ar
CN
CN
(iii)
N
N
N
N
7
NHNH2
O
H
10
Ar
NH
(iv)
(v)
S
S
NH
N
N
H
11
Ar
CN
N
N
N
CH3
H3C
12
Ar
CN
(vi)
H
N
N
N
O
13
H2N
(i) HCONH2; (ii) HCOOH; (iii)ClCH2COOEt, pyridine ; (iv)CS2, alc. KOH; (v) CH3COCH2COCH3, EtOH; (vi)
CNCH2COOEt, EtOH
Scheme 3 Synthesis of fused and nonfused tetrahydroquinoline derivatives
1 3

Synthesis, antileishmanial and cytotoxicity activities…
followed by decarboxylation to aford N-acetyl-N′-[4-(4-methoxyphenyl)-5,6,7,8-
tetrahydroquinoline-2-yl]acetohydrazide (15).
Furthermore, when 2-hydrazinoquinoline 7 was treated with benzoyl chloride
and/or triethyl orthoformate, the isolated products have been identifed as quino-
lin-2-ylbenzohydrazide 16 and tetrahydroquinoline-3-carbonitrile derivatives 17,
respectively. It seems that compound 17 was formed as a result of nucleophilic sub-
stitution on the electronically defcient carbon of triethyl orthoformate followed by
demethylation (cf. Scheme 4).
We studied the reaction of ethyl acetoacetate with 2-hydrazinoquinoline 7 in
ethanol in the presence of a basic catalyst, namely, piperidine and/or in absence
of it. In the frst case, the isolated product has been identifed as ethyl 2-(imino(4-
(4-methoxyphenyl)-2-hydrazinyl-5,6,7,8-tetrahydroquinolin-3-yl)methyl)-3-oxobu-
tanoate (18). According to our speculation, the presence of piperidine lead to for-
mation of the carbanion from the electronically defcient methylene group fanked
between the two carbonyl groups of ketone and ester of the reagent. The generating
Ar
CN
(i)
N(COCH3)2
N
14
N
H
Ar
(ii)
N(COCH3)2
CN
N
N
H
15
Ar
Ar
N
CN
(iii)
H
N
H
O
N
16
N
Ph
NHNH2
7
Ar
CN
NH
(iv)
N
N
CH OH
COCH3
17
Ar NH
(v)
COOEt
NH
N
18
NH2
Ar
CN
(vi)
COOEt
CH3
N
N
N
H
19
(i) Ac2O/ reflux; (ii) Ac2O / fusion; (iii)PhCOCl, EtOH ; (iv)CH(OEt)3; (v) EtOCOCH2COCH3, EtOH, piperidine; (vi)
EtOCOCH2COCH3, EtOH
Scheme 4 Reactions of 2-hydrazinyl-tetrahydroquinoline-3-carbonitrile 7 with diferent electrophiles
1 3

H. M. F. Madkour et al.
carbanion subsequently attacked the cyano group to form the fnal product. When
the same reaction was conducted in the absence of piperidine, the N-nucleophile
amino group attacked the carbonyl carbon of the ketonic group as an electrophilic
center to aford ethyl 2-(2-(3-cyano-4-(4-methoxyphenyl)-5,6,7,8-tetrahydroquino-
lin-2-yl)hydrazono)propanoate (19).
Biological activity
Antileishmanial activity
In the present studies on heterocyclic compounds against L. major leishmania,
it is evident that from (Table 1) a series of heterocyclic compounds showed tre-
mendous activity toward L. major leishmania. Compound 5, 10, 13 and 19 have
shown signifcant activity against L. major with IC50 values of 0.58
0.08 and
0.59
0.07 µg/ml, respectively, compared to Amphotericin B (standard drug)
IC50 value (0.56 0.20 µg/ml). On the other hand, further compounds 4, 6–8 and
11–17 showed a good activity against L. major with IC50 values of 0.60
0.27
Table 1 % Inhibition of
Compounds numbers
L. major leishma-
compounds 1–19 against L.
major leishmania
nia, (µg/ml SD)
1
0.80 0.09
0.82 0.01
0.77 0.09
0.69 0.09
0.59 0.09
0.63 0.09
0.62 0.09
0.67 0.09
0.72 0.09
0.59 0.09
0.62 0.09
0.65 0.09
0.64 0.09
0.68 0.09
0.65 0.09
0.60 0.09
0.61 0.09
0.58 0.09
0.57 0.09
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
Standard drug IC50 (µg/ml SD) Amphotericin 0.56 0.20
B
%
Inhibition activity: 0.99
0.00 = non-signifcant, 0.95–
0.80 = low, 0.79–0.70 = moderate, 0.69–0.60 = good, < 0.59–
0.56 = signifcant
1 3

Synthesis, antileishmanial and cytotoxicity activities…
and 0.69 0.03 µg/ml, respectively. The rest of the compounds have shown mod-
erate to low activity against L.major parasite with IC50 values for compounds 3
(0.77 0.09 µg/ml) and 9 (0.72 0.09 µg/ml). L. major leishmania showed resist-
ance toward compounds 1 and 2.
Cytotoxicity activity by brine‑shrimp lethality assay
The crown gall is a neoplastic disease of plants which is initiated by the Gram-pos-
itive bacteria Agrobacterium tumefaciens. Since the mechanism of tumor induction
resembles that in animals, this test has been used previously to prescreen antitu-
mor activity of natural and synthetic compounds. According to the data shown in
Table 2, most of the test compounds of this series 1–19 showed signifcant levels
of tumor inhibition. Compound 19 showed 100% tumor inhibition that is compara-
ble to the standard drug Vincristine (100% tumor inhibition). Compound 4 showed
21.42%, compound 6 showed 29.33%, compound 7, 8 showed 29.33%, compound
11 showed 24. 05%, compound 13 showed 21.42%, compound 14 showed 37.58%,
Table 2 Antitumor activity of
Compounds no.
Average number of
tumorsa SE
% Inhibition
of tumorsb,c
compounds 1–19
1
8.5 0.01
7.1 0.03
8.2 0.07
6.7 0.07
7.5 0.07
5.3 0.84
5.3 0.84
5.1 0.33
7.5 0.12
6.9 0.07
6.3 0.55
7.2 0.09
6.7 0.07
5.5 0.66
7.2 0.02
8.7 0.07
5.1 0.38
6.4 1.98
0.0 0.0
16.53
18.22
16.42
21.42
18.53
29.33
29.33
29.01
18.47
19.79
24.05
17.62
21.42
37.58
18.40
17.13
29.89
43.59
100
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
Vincristine
0.0 0.0
100
Vehicle control: DMSO
8.3 0.931
aPotato disc antitumor assay, concentration: 1000 µg/ml in DMSO
bMore than 20% tumor inhibition is signifcant
cData represents mean value of 15 replicates
1 3

H. M. F. Madkour et al.
compound 17 showed 29.89%, compound 18 showed 43.59%, and tumor inhibition
that is comparable to the standard drug Vincristine (100% tumor inhibition).
Experimental
Melting points measurement was made on Gallenkamp melting point apparatus and
is uncorrected. The IR spectra were noted in (KBr) potassium bromide disks on a
Pye Unicam SP-3-300 IR spectrophotometer. The 1H-NMR experiment was done at
300 and 400 MHz on a Varian Mercury VX-300 NMR spectrometer using TMS
as the internal standard in deuterated chloroform or deuterated dimethylsulphide.
Chemical shifts are quoted δ. The mass spectra were measured on a Shimadzu
GCMS-QP-1000EX mass spectrometer at 70 eV. All spectral measurements were
carried out at the Central Laboratory of Ain-Shams University and the Main Defense
Chemical Laboratory, Egypt. Biological activity was carried out in the Department
of Pharmacy, COMSATS Institute of Information Technology, and Abbottabad,
Pakistan. All the newly synthesized compounds gave adequate elemental analyses.
The purity of the newly synthesized compounds has been checked through TLC.
Synthesis
Method A
4‑(4‑Methoxyphenyl)‑2‑oxo‑1,2,5,6,7,8‑hexahydroquinoline‑3‑carbonitrile
(1) and 4‑(4‑methoxyphenyl)‑2‑1,2,3,4,5,6,7,8‑octahydroquinoline‑3‑carbon‑
itrile (2) A mixture of cyclohexanone (10 mmol, 0.98 ml), ethyl cyanoacetate
(10 mmol, 1.14 ml), 4-methoxybenzaldehyde (10 mmol, 1.36 ml) and ammonium
acetate (80 mmol, 6.16 g) in absolute ethanol (30 ml) was heated under refux for
9 h. The resultant precipitate was subjected to fltration on heat, and recrystallized
from dioxane to give octahydroquinolinone 2 as yellow crystals, mp 208–210 °C,
(Lit. 212–214 °C) [24], yield 75%. The fltrate obtained was allowed to cool at room
temperature, and the solid product was collected, dried and recrystallized from etha-
nol to give 1 as a pale yellow crystal, mp 287–289 °C, (Lit. 291–293 °C) [24], yield
25%.
Method B
4‑(4‑methoxyphenyl)‑2‑oxo‑1,2,5,6,7,8‑hexahydroquinoline‑3‑carbonitrile
(1) A mixture of cyclohexanone (10 mmol, 0.98 ml), cyanoacetamide (10 mmol,
0.8 g), 4-methoxybenzaldehyde (10 mmol, 1.36 ml) and ammonium acetate
(80 mmol, 6.16 g) in absolute ethanol (30 ml) was heated at refux for 7 h. The mix-
ture left to cool at room temperature, and the solid product was collected, dried and
recrystallized from ethanol to give 1 as a pale yellow crystal, mp 287–289 °C, yield
63%.
1 3

Synthesis, antileishmanial and cytotoxicity activities…
2‑Amino‑(4‑methoxyphenyl)‑5,6,7,8‑tetrahydroquinoline‑3‑carbonitrile (3)
A
mixture of cyclohexanone (10 mmol, 0.98 ml), malononitrile (10 mmol, 2.2 g),
4-methoxybenzaldehyde (10 mmol, 1.36 ml) and ammonium acetate (80 mmol,
6.16 g) in absolute ethanol (30 ml) was heated at refux for 9 h, then left to cool at
room temperature. The solid product was collected, dried and recrystallised from
dioxane to give enaminonitrile 3 as brown crystals, mp 249–250 °C, yield 65% [25,
26].
2‑Chloro‑4‑(4‑methoxyphenyl)‑5,6,7,8‑tetrahydroquinoline‑3‑carbonitrile
(4) A mixture of octahydroquinolinone 2 (5 mmol, 1.4 g), phosphorous pentachlo-
ride (5 mmol, 1.25 g) and phosphorous oxychloride (5 mmol, 3.5 ml) was refuxed
in a water bath for 6 h., then allowed to cool and poured into ice–cold water. The
separated material was collected by fltration, washed with water, dried and recrys-
tallised from ethanol to give 4 pale brown crystals, mp 161–163 °C, (Lit. 170 °C)
[27], yield 75%. FT-IR (KBr, cm−1): disappearance of νNH, 3068 νCH aromatic, 2933
1
νCH aliphatic, 2227 νC≡N, 1660 νC=N, 1608 νC=C. HNMR (300 MHz, DMSO-d6):
7.35–7.08 (m, 4H, Ar–H), 3.84 (s, 3H, OCH3) 2.95–1.65 (m, 8H, cyclohexene moi-
ety). Anal. Calcd. for C17H15ClN2O (298.77): C, 68.34; H, 5.06; Cl, 11.87; N, 9.38.
Found: C, 68.12; H, 5.14; Cl, 11.76; N, 9.25.
5‑(4‑Methoxyphenyl)‑6,7,8,9‑tetrahydrotetrazolo[1,5‑a]quinoline‑4‑carbonitrile
(5) To a solution of tetrahydroquinoline 4 (5 mmol, 1.5 g) in DMF (20 ml), sodium
azide (5 mmol 0.3 g) was added then refuxed for 4 h, left to cool, and poured into
ice–cold water. The separated material was collected by fltration, washed with
water, dried and recrystallized from methanol to give tetrazolo[1,5-a]quinoline 5
as pale orange crystals, mp 215–217 °C, yield 47% FT-IR (KBr,cm−1): 3069 νCH
1
aromatic, 2933 νCH aliphatic 2209 νC≡N, 1668 νC=N. HNMR (400 MHz, DMSO):
7.34–7.07 (m, 4H, Ar–H), 3.89 (s, 3H, OCH3), 2.93–1.68 (m, 8H, cyclohexane ring
̇
protons). MS (m/z (%)): 305 (M+, 20.11), 297 (19.22), 206 (100.00), 194 (17.57),
132 (18.97), 119 (10.56), 68 (4.62). Anal. Calcd. for C17H15N5O (305.33): C, 66.87;
H, 4.95; N, 22.94. Found: C, 66.67; H, 4.78; N, 22.82.
1,4‑Bis(3‑cyano‑4‑(4‑methoxyphenyl)‑5,6,7,8‑tetrahydroquinolin‑2‑yl)thio‑
semicarbazide (6) A mixture of tetrahydroquinoline 4 (5 mmol, 1.5 g) and thio-
semicarbazide (5 mmol, 0.5 g) in ethanol (20 ml) was heated and refuxed for 10 h,
then the mixture was left to cool to room temperature. The solid product was col-
lected, dried and recrystallised from dioxane to give tetrahydroquinoline derivative
6 as pale brown crystals, mp 231–233 °C, yield 65%. FT-IR (KBr, cm−1): 3349 νNH
,
1
3069 νCH aromatic, 2933 νCH aliphatic, 2221 νC≡N, 1607 νC=N, 1250 νC=S. HNMR
(400 MHz, DMSO-d6): 8.98 (s, 2H, 2NH, D2O exchangeable), 7.50–7.15 (m, 8H,
Ar–H), 4.45 (s, 1H, NH, D2O exchangeable), 3.80 (s, 6H, OCH3), 2.92–1.02 (m,
̇
+
16H, cyclohexane ring protons). MS (m/z (%)): 556 (M-2OCH3 + 2H] , 0.87), 533
(4.55), 438 (22.27), 437 (23.49), 421 (9.90), 386 (3.86), 347 (7.97), 270 (12.70),
246 (13.16), 244 (12.24), 220 (100.00), 193 (25.65), 176 (47.95). Anal. Calcd. for
1 3

H. M. F. Madkour et al.
C35H33N7O2S (615.75): C, 68.27; H, 5.40; N, 15.92; S, 5.21. Found: C, 68.14; H,
5.32; N, 15.76; S, 5.15.
2‑Hydrazinyl‑4‑(4‑methoxyphenyl)‑5,6,7,8‑tetrahydroquinoline‑3‑carbonitrile
(7) A mixture of tetrahydroquinoline 4 (5 mmol, 1.5 g) and hydrazine hydrate
(10 mmol, 0.5 ml) in ethanol (20 ml) was heated under refux for 12 h, then the
mixture was allowed to cool. The solid residue was collected, dried and recrystal-
lised from dioxane to give 2-hydrazinoquinoline derivative 7 as pale orange crystals,
mp 275–277 °C, yield 54%. FT-IR (KBr, cm−1): 3420, 3350 νNH, νNH2, 3070 and
1
3005 νCH aromatic, 2934 νCH aliphatic, 2226 νC≡N,1647 νC=N. HNMR (300 MHz,
CDCl3): 11.70 (s, 1H, NH, D2O exchangeable), 7.27- 7.07 (m, 4H, Ar–H), 4.02 (s,
2H, NH2, D2O exchangeable), 3.56 (s, 3H, OCH3), 2.93-1.68 (m, 8H, cyclohexane
̇
ring protons). MS (m/z (%)): 294 (M+, 6.71), 263 (1.44), 187 (3.94), 173 (16.84),
132 (11.7), 91 (100.00), 90 (4.56). Anal. Calcd. for C17H18N4O (294.35): C, 69.37;
H, 6.16; N, 19.03. Found: C, 69.21; H, 6.01; N, 18.94.
5‑(4‑Methoxyphenyl)‑1‑oxo‑1,2,6,7,8,9‑hexahydro[1,2,4]triazolo[4,3‑a]quino‑
line‑4‑carbonitrile (8) A solution of 2-hydrazinoquinoline 7 (5 mmol, 1.4 g) in
formamide was heated under refux for 6 h, then left to cool, and transferred into
ice–cold water. The crude solid residue was collected by fltration, washed, dried
and recrystallised from ethanol to give triazolo[4,3-a]quinoline derivative 8 as pale
green crystals, mp 229–250 °C, yield 81%. FT-IR (KBr, cm−1): 3385 νNH, 3080 νCH
aromatic, 2935νCH aliphatic, 2219 νC≡N, 1688νC=O, 1654 νC=N, 1607 νC=C. 1HNMR
(300 MHz, DMSO-d6): 12.29 (s, 1H, NH, D2O exchangeable), 7.36-7.04 (m, 4H,
Ar–H), 3.81 (s, 3H, OCH3), 2.72-1.55 (m, 8H, cyclohexane ring protons). MS (m/z
̇
(%)): 320 (M+, 4.63), 294 (6.45), 280 (100.00), 199 (1.68), 138 (11.30), 133 (84.31),
83 (5.39), 56 (6.56). Anal. Calcd. for C18H16N4O2 (320.35): C, 67.49; H, 5.03; N,
17.49. Found: C, 67.35; H, 5.12; N, 17.32.
5‑(4‑Methoxyphenyl)‑6,7,8,9‑tetrahydro[1,2,4]triazolo[4,3‑a]quinoline‑4‑car‑
bonitrile (9) A solution of 2-hydrazinoquinoline 7 (5 mmol, 1.4 g) in formic acid
was heated under refux for 8 h, allowed to cool and transferred into ice–cold water.
The separated material was collected by fltration, washed, dried and recrystallised
from ethanol to give triazolo[4,3-a]quinoline derivative 9 as pale brown crystals,
mp 220–222 °C, yield 67%. FT-IR (KBr, cm−1): 3011 νCH aromatic, 2936 νCH ali-
1
phatic, 2220 νC≡N, 1648 νC=N, 1606 νC=C. HNMR (400 MHz, DMSO-d6): 8.25 (s,
1H, C–H olefnic), 7.67–6.82 (m, 4H, Ar–H), 3.90 (s, 3H, OCH3), 2.81–1.55 (m, 8H,
̇
cyclohexane ring protons). MS (m/z (%)): 304 (M+, 4.66), 272 (2.34), 252 (4.35),
199 (5.05), 71 (100.00), 57 (81.08). Anal. Calcd. for C18H16N4O (304.35): C, 71.04;
H, 5.30; N, 18.41. Found: C, 71.12; H, 5.25; N, 18.22.
6‑(4‑Methoxyphenyl)‑1‑oxo‑2,3,7,8,9,10‑hexahydro‑1H‑[1,2,4]triazino[4,3‑a]
quinoline‑5‑carbonitrile (10) A mixture of 2-hydrazinoquinoline 7 (5 mmol,
1.4 g) and ethyl chloroacetate (5 mmol, 0.6 ml) in pyridine (25 ml) was heated under
refux for 18 h. The reaction mixture is allowed to cool then neutralized with dilute
1 3

Synthesis, antileishmanial and cytotoxicity activities…
hydrochloric acid, the product was collected by fltration, washed with water, dried
and recrystallised from ethanol to give triazino[4,3-a]quinoline 10 as pale brown
crystals, mp 173 dec., yield 76%. FT-IR (KBr, cm−1): 3433, 3377 νNH, 3069 νCH
aromatic, 2999 νCH aliphatic, 2216 νC≡N, 1722 νC=O, 1668 νC=N. 1HNMR (400 MHz,
DMSO-d6): 11.73 (s, 1H, NH, D2O exchangeable), 7.34–7.06 (m, 4H, Ar–H), 3.88
(s, 2H, –COCH2), 3.82 (s, 3H, OCH3), 2.9–1.65 (m, 8H, cyclohexane ring pro-
tons). MS (m/z (%)): 338 (M + 4, 7.06), 334 (7.45), 276 (18.28), 226 (18.93), 199
(12.25), 170 (10.67), 135 (20.25), 126 (100.00), 97 (9.78), 58 (11.34). Anal. Calcd.
for C19H18N4O2 (334.37): C, 68.25; H, 5.43; N, 16.76. Found: C, 68.01; H, 5.23; N,
16.54.
5‑Imino‑6‑(4‑methoxyphenyl)‑1,2,7,8,9,10‑hexahydro[1,3,4]thiadiazepino[5,6‑b]
quinoline‑3(5H)‑thione (11) A solution of 2-hydrazinoquinoline 7 (5 mmol,
1.4 g) in potassium hydroxide (5 mmol, 0.28 g) absolute ethanol (20 ml), and carbon
disulfde (15 mmol, 1.14 ml) were mixed. The mixture was heated in a water bath
for 10 h, then left to cool, poured into water, and neutralized with dilute hydrochlo-
ric acid. Separated solid was collected by fltration, washed, dried and recrystallised
from methanol to give thiadiazepino[5,6-b]quinoline derivative 11 as pale brown
crystals, mp over 300 °C, yield 70%. FT-IR (KBr, cm−1): 3306, 3192 νNH, 3029 νCH
aromatic, 2937 νCH aliphatic, disappearance of νC≡N, 1615 νC=N, 1245 νC=S. 1HNMR
(300 MHz, DMSO-d6): 11.73 (s, 1H, NH, D2O exchangeable), 7.24- 7.07 (m, 4H,
Ar–H), 4.05 (s, 1H, NH, D2O exchangeable), 3.82 (s, 3H, OCH3), 3.52 (s, 1H, NH,
D2O exchangeable), 2.92-1.65 (m, 8H, cyclohexane ring protons). MS (m/z (%)):
̇
370 (M+, 0.91), 314 (12.05), 209 (2.93), 119 (100.00), 107 (36.61), 56 (5.08), 52
(17.56). Anal. Calcd. for C18H18N4OS2 (370.49): C, 58.35; H, 4.90; N, 15.12; S,
17.31. Found: C, 58.22; H, 4.74; N, 15.01; S, 17.26.
2‑(3,5‑Dimethyl‑1H‑pyrazol‑1‑yl)‑4‑(4‑methoxyphenyl)‑5,6,7,8‑tetrahydroquin‑
oline‑3‑carbonitrile (12) A mixture of 2-hydrazinoquinoline 7 (5 mmol, 1.4 g)
and acetylacetone (5 mmol, 0.5 ml) in absolute ethanol (25 ml) was heated at refux
for 17 h, then left to cool. The solid product was collected, dried and recrystallised
from benzene to give tetrahydroquinoline derivative 12 as pale yellow crystals, mp
over 300 °C, yield 55%. FT-IR (KBr, cm−1): 3035 νCH aromatic, 2932 νCH aliphatic,
1
2217 νC≡N, 1670 νC=N. HNMR (400 MHz, DMSO-d6): 7.61- 7.06 (m, 5H, Ar–H),
3.84 (s, 3H, OCH3), 2.98-2.02 (m, 8H, cyclohexane ring protons), 1.22 (s, 6H,
2CH3). MS (m/z (%)): 360 (M + 2, 4.16), 258 (100.00), 332 (2.22), 302 (2.13), 263
(4.78), 251 (18.07), 226 (2.27), 157 (8.15), 95 (38.08). Anal. Calcd. for C22H22N4O
(358.44): C, 73.72; H, 6.19; N, 15.63. Found: C, 73.56; H, 6.05; N, 15.58.
2‑(5‑Amino‑3‑oxo‑2,3‑dihydropyrazol‑1‑yl)‑4‑(4‑methoxy‑phenyl)‑5,6,7,8‑tet‑
rahydro‑quinoline‑3‑carbonitrile (13) A mixture of 2-hydrazinoquinoline 7
(5 mmol, 1.4 g) and ethyl cyanoacetate (5 mmol, 0.6 ml) in ethanol (25 ml) was
heated under refux for 13 h, then left to cool. The precipitated solid residue was
collected, dried and recrystallised from dioxane/water to give 13 as brown crys-
tals, mp 173–175 °C, yield 63%. FT-IR (KBr, cm−1): 3300, 3194, 3143 νNH2, νNH
,
1 3

H. M. F. Madkour et al.
1
3031 νCH aromatic, 2934 νCH aliphatic, 2221 νC≡N, 1642 νC=O, 1605 νC=N. HNMR
(300 MHz, DMSO-d6): 11.73 (s, 1H, NH, D2O exchangeable), 7.45- 7.01 (m, 4H,
Ar–H), 4.54 (s, 1H, pyrazolone-H), 3.84 (s, 3H, OCH3), 2.11 (s, 2H, NH2, D2O
exchangeable), 2.92-1.65 (m, 8H, cyclohexane ring protons). MS (m/z (%)): 361
̇
(M+, 6.43), 294 (86.67), 280 (30.37), 263 (7.86), 98 (16.08), 43 (100.00). Anal.
Calcd. for C20H19N5O2 (361.4): C, 66.47; H, 5.30; N, 19.38. Found: C, 66.25; H,
5.16; N, 19.23.
N‑Acetyl‑N′‑[3‑cyano‑4‑(4‑methoxyphenyl)‑5,6,7,8‑tetrahydroquinolin‑2‑yl]
acetohydrazide (14) A solution of 2-hydrazinoquinoline 7 (5 mmol, 1.4 g) in
acetic anhydride (10 ml) was refuxed for 7 h, then transferred into ice/cold water
along with stirring. The crude solid residue that deposited was collected by fltra-
tion, washed, dried and recrystallised from methanol to give acetohydrazide deriva-
tive 14 as pale brown crystals, mp 230–232 °C, and yield 72%. FT-IR (KBr, cm−1):
3199 νNH, 3070 νCH aromatic, 2935 νCH aliphatic, 2226 νC≡N, 1729 νC=O imide,
1
1607 νC=N. HNMR (400 MHz, DMSO-d6): 9.83 (s, 1H, NH, D2O exchangeable),
7.37–6.97 (m, 4H, Ar–H), 3.85 (s, 3H, OCH3), 3.06 (s, 6H, (COCH3)2), 2.9-1.77 (m,
8H, cyclohexane ring protons). MS (m/z (%)): 380 (M + 2, 1.74), 334 (5.07), 294
(100.00), 284 (1.66), 271 (3.07), 246 (12.76), 199 (8.79), 181 (4.16), 179 (7.15), 158
(2.70). Anal. Calcd. for C21H22N4O3 (378.42): C, 66.65; H, 5.86; N, 14.81. Found:
C, 66.54; H, 5.72; N, 14.69.
N‑Acetyl‑N′‑[4‑(4‑methoxyphenyl)‑5,6,7,8‑tetrahydroquinolin‑2‑yl]aceto‑
hydrazide (15) A solution of 2-hydrazinoquinoline 7 (5 mmol, 1.4 g) in acetic
anhydride (5 ml) was fused for 7 h at 200 °C, then transferred into ice/cold water
along with stirring. The crude solid residue that deposited was collected by fltra-
tion, washed, dried and recrystallised from dioxine/water to give acetohydrazide
derivative 15 as pale brown crystals, mp 160–162 °C, and yield 72%. FT-IR (KBr,
cm−1): 3175 νNH, 3011 νCH aromatic, 2937 νCH aliphatic, 1728 νC=O imide, 1610
ν
C=N. 1HNMR (400 MHz, DMSO-d6): 11.80 (s, 1H, NH, D2O exchangeable), 7.34–
7.01 (m, 5H, Ar–H), 3.85 (s, 3H, OCH3), 2.32 (s, 6H, (COCH3)2), 3.27–1.83 (m,
̇
8H, cyclohexane ring protons). MS (m/z (%)): 353 (M+, 1.80), 322 (10.79), 294
(100.00), 246 (3.76), 215 (2.21), 156 (1.00), 115 (4.62), 102 (3.08). Anal. Calcd.
for C20H23N3O3 (353.41): C, 67.97; H, 6.56; N, 11.89. Found: C, 67.85; H, 6.42; N,
11.75.
N′‑(3‑Cyano‑4‑(4‑methoxyphenyl)‑5,6,7,8‑tetrahydroquinolin‑2‑yl)benzohy‑
drazide (16) A mixture of 2-hydrazinoquinoline 7 (5 mmol, 1.4 g) and benzoyl
chloride (5 mmol, 0.7 ml) in absolute ethanol (25 ml) was heated at refux for 5 h,
then left to cool. The solid product was collected, dried and recrystallised from
methanol to give benzohydrazide derivative 16 as pale orange crystals, mp 244–
246 °C, and yield 75%. FT-IR (KBr, cm−1): 3199 νNH, 3053 νCH aromatic, 2958 νCH
aliphatic, 2218 νC≡N, 1666 νC=O, 1632 νC=N. 1HNMR (400 MHz, DMSO-d6): 10.64
(s, 2H, 2NH, D2O exchangeable), 7.91–7.48 (m, 9H, Ar–H), 3.54 (s, 3H, OCH3),
̇
2.9–1.77 (m, 8H, cyclohexane ring protons). MS (m/z (%)): 398 (M+, 2.04), 291
1 3

Synthesis, antileishmanial and cytotoxicity activities…
(5.85), 278 (2.02), 120 (11.93), 108 (70.47), 101 (100.00), 76 (93.33). Anal. Calcd.
for C24H22N4O2 (398.46): C, 72.34; H, 5.57; N, 14.06. Found: C, 72.15; H, 5.43; N,
14.18.
4‑(4‑Methoxyphenyl)‑2‑(2‑hydroxymethylenehydrazinyl)‑5,6,7,8‑tetrahydroqui‑
noline‑3‑carbonitrile (17) A solution of 2-hydrazinoquinoline 7 (5 mmol, 1.4 g),
in triethyl orthoformate (10 ml) was refuxed for 19 h, and left to cool. The solid
product was collected, dried and recrystallised from pet 80–100 to give quinolin-
2-ylhydrazonoformate derivative 17 as pale red crystals, mp 193–195 °C, and yield
75%. FT-IR (KBr, cm−1): 3454 νOH, 3301νNH, 3029 νCH aromatic, 2932 νCH ali-
1
phatic, 2211 νC≡N, 1607 νC=N. HNMR (400 MHz, DMSO-d6): 11.71 (s, 1H, NH,
D2O exchangeable), 7.46–7.03 (m, 5H, Ar–H & N = CH), 3.81 (s, 3H, OCH3), 3.28
(s, 1H, OH, D2O exchangeable), 2.90–1.61 (m, 8H, cyclohexane ring protons). MS
(m/z (%)): 323 (M + 1, 1.21), 308 (8.98), 267 (30.86), 266 (13.67), 240 (15.44),
220 (30.53), 172 (11.19), 165 (14.89), 151 (11.64), 136 (16.89), 43 (100.00). Anal.
Calcd. for C18H18N4O2 (322.36): C, 67.07; H, 5.63; N, 17.38. Found: C, 67.14; H,
5.50; N, 17.24.
Ethyl
2‑(imino(4‑(4‑methoxyphenyl)‑2‑hydrazinyl‑5,6,7,8‑tetrahydro‑
quinolin‑3‑yl)me‑thyl)‑3‑oxobutanoate (18) A mixture of 2-hydrazinoquino-
line 7 (5 mmol, 1.4 g) and ethyl acetoacetate (5 mmol, 0.7 ml), and two drops of
piperidine in absolute ethanol (25 ml) was refuxed for 15 h, then allowed to cool.
The resultant solid product was collected, dried and recrystallised from methanol
to give 2-hydrazinoquinoline derivative 18 as pale red crystals, mp over 300 °C,
and yield 65%. FT-IR (KBr, cm−1): 3442, 3202 νNH2, NH, 3027 νCH aromatic, 2959
1
νCH aliphatic, 1727 νC=O ester, 1700 νC=O ketone, 1605 νC=N. HNMR (400 MHz,
DMSO-d6): 12.94 (s, 1H, NH, D2O exchangeable), 7.46–6.97 (m, 4H, Ar–H), 5.79
(s, 1H, CHCOCH3), 4.60 (s, 2H, NH2, D2O exchangeable), 4.20 (s, 1H, NH, D2O
exchangeable), 3.86 (s, 3H, OCH3), 3.79 (q, 2H, CH2CH3), 2.45 (s, 3H, COCH3),
2.34-1.01 (m, 8H, cyclohexane ring protons), 0.81 (t, 3H, CH2CH3). MS (m/z (%)):
̇
424 (M+, 1.82), 368 (0.85), 317 (2.23), 265 (0.73), 164 (100.00), 157 (3.21), 107
(48.09). Anal. Calcd. for C23H28N4O4 (424.49): C, 65.08; H, 6.65; N, 13.20. Found:
C, 65.23; H, 6.54; N, 13.08.
Ethyl
2‑(2‑(3‑cyano‑4‑(4‑methoxyphenyl)‑5,6,7,8‑tetrahydronaphthalen‑2‑yl)
hydrazono)prop‑anoate (19) To a solution of 2-hydrazinoquinoline 7 (5 mmol,
1.4 g) in absolute ethanol (25 ml), ethyl acetoacetate (5 mmol, 0.7 ml), was added,
then refux of the reaction mixture was done for 15 h, and left to cool. The solid
product was collected, dried and recrystallised from methanol to give 19 as pale
red crystals, mp over 300 °C, and yield 65%. FT-IR (KBr, cm−1): 3194νNH, 3050
1
νCH aromatic, 2934 νCH aliphatic, 2214 νC≡N, 1735 νC=O ester, 1658 νC=N. HNMR
(400 MHz, DMSO-d6): 7.37–6.99 (m, 4H, Ar–H), 4.20 (q, 2H, CH2CH3), 3.88 (s,
3H, OCH3), 3.44 (s, 1H, NH, D2O exchangeable), 2.82-1.57 (m, 8H, cyclohexane
̇
ring protons), 1.30 (t, 3H, CH2CH3), 0.84 (s, 3H, CH3). MS (m/z (%)): 391 (M+,
2.39), 335 (1.59), 251 (22.41), 223 (0.29), 192 (8.32), 105 (100.00), 77 (69.47).
1 3

H. M. F. Madkour et al.
Anal. Calcd. for C22H24N4O3 (392.45): C, 67.33; H, 6.16; N, 14.28. Found: C, 67.15;
H, 6.07; N, 14.04.
Biological activity
Antileishmanial activity
Antileishmanial activity were checked for all the synthesized heterocyclic com-
pounds and 1–19 were primarily screened distinctively for culture of L. major [28,
29]; 1 mg of every compound was dissolved using solvent DMSO (1 ml) and 1 mg
of Amphotericin B was also solubilized in 1 ml of DMSO. Then, 180 µl of medium
was poured in various wells of 96-well plates. Also, 20 µl of the tetrahydroquinoline
derivatives solution was then added into the medium and diluted serially. Parasites
at log phase for 3 min were centrifuged at 3000 rpm. Fresh culture medium was
used for diluting the parasites to a fnal density of 2 × 106 cells/ml. In all wells,
100 µl of parasite culture was added. Negative and standard drugs were maintained
having DMSO and Amphotericin B. For positive and negative controls, three rows
were left empty. DMSO was diluted serially in medium in case of negative controls
while in positive control there were diferent concentrations of standard antileish-
manial compound, e.g., Amphotericin B. Microtiter plates were incubated for 72 h
at 24 °C. Every assay was in duplicate. Then 15 µl of test culture was transferred
after 72 h, for growth in a Neubauer counting chamber and live promastigotes were
counted using a light microscope.
Cytotoxicity activity by brine‑shrimp lethality assay
The brine shrimp cytotoxicity assay was used by following the procedure described
[30]. By dissolving 34 g of sea salt (Aquarium System, OH, UISA) in 1000 ml of
distilled water with regular stirring then artifcial sea water was prepared. Forceful
shaking on a magnetic stirrer was done to verify the solution in an open beaker for
two hours. Then 50 mg of Artemia salina Leach eggs (Artemia, Inc., CA, USA)
was added in a hatching chamber. Seawater was used for hatching of Artemia salina
in a shallow quadrilateral dish (22 × 32 cm) previously flled with prepared (brine
shrimp eggs) which comprised two compartments, one was large and the other was
a small compartment. Both the compartments were separated by a wall consisting of
several holes of 2 mm in diameter, with artifcial sea water in the large compartment
on which eggs were spread on the surface. The large compartment was covered with
aluminum foil so that there was darkness in that compartment. The smaller compart-
ment was lit with a lamp. After 24–26 h the hatching process started and the newly
hatched nauplii (brine shrimp larvae) traveled towards the smaller compartment due
to the presence of light. The nauplii were collected in a beaker with the help of a
Pasteur pipette. Three concentrations of the tested samples were dissolved in metha-
nol (10, 100 and 1000 µg/ml) and were used against brine shrimp larvae; the vials
and the control containing 500 μl of solvent were allowed to evaporate to dryness in
about 48 h at room temperature and then the rate of death at all concentrations was
1 3

Synthesis, antileishmanial and cytotoxicity activities…
observed. To check the number of deaths, each sample quantity taken was 0.5 ml in
a 20 ml vial. Furthermore, additional 2 ml artifcial sea water was added to evapo-
rate the solvent. After this 30 shrimp were transferred to each vial with fnal vol-
ume adjusted to 5 ml. They were kept under forescence lighting at a temperature of
25 °C for a time period of 24 h. Three replicates were prepared for each dose level.
The negative control solution was the same saline solution used to prepare the stock
test sample solution. Potassium dichromate was used as standard toxicant and dis-
solved in artifcial seawater, to obtain concentrations of 1000, 100, and 10 ppm. A
Finney computer program was used to evaluate ED50 after the percentage survival
was calculated.
Acknowledgements The authors gratefully thank Dr. Muhammad Ashfaq and Dr. Yasser MSA Alkah-
raman, Department of Pharmacy, COMSATS Institute of Information Technology, Abbottabad, Pakistan
for performing antileishmanial and cytotoxicity screening of the synthesized compounds.
References
1. O.I. Abd El-Salam, D.A. Abou Ella, N.S. Ismail, M. Abdullah, Pharmazie 64(3), 147 (2009)
2. K. Tsuji, G.W. Spears, K. Nakamura, T. Tojo, N. Seki, A. Sugiyama, M. Matsuo, Bioorg. Med.
Chem. Lett. 12(1), 85 (2002)
3. I. Tomasoli, M. Pudlo, C. de Los Rios, E. Soriano, I. Colmena, L. Gandia, L. Rivas, A. Samadi, J.
Marco-Contelles, B. Refouvelet, Eur. J. Med. Chem. 46, 1 (2011)
4. M.M. Ghorab, F.A. Ragab, M.M. Hamed, Eur. J. Med. Chem. 44, 4211 (2009)
5. S.I. Alquasoumi, A.M. Al-Taweel, A.M. Alafeefy, M.M. Ghorab, E. Noaman, Eur. J. Med. Chem.
45(5), 1849 (2010)
6. N. Yamada, S. Kadowaki, K. Takahashi, K. Umezu, Biochem. Pharmacol. 44, 1211 (1992)
7. D.S. Su, J.J. Lim, E. Tinney, B.L. Wan, M.B. Young, K.D. Anderson, D. Rudd, V. Munshi, C. Bah-
nck, Bioorg. Med. Chem. Lett. 19, 5119 (2009)
8. R.T. Skerlj, G.J. Bridger, A. Kaller, E.J. McEachern, J.B. Crawford, Y. Zhou, J. Med. Chem. 53,
3376 (2010)
9. C. Ramesh, T.K. Nayak, R. Burai, M.K. Dennis, H.J. Hathaway, L.A. Sklar, E.R. Prossnitz, J.B.
Arterburn, J. Med. Chem. 53, 1004 (2010)
10. H.F. de Freitas, M.S. Castilho, Med. Chem. 8(2), 252 (2012)
11. T.A. Rano, E. Sieber-McMaster, P.D. Pelton, M. Yang, K.T. Demarest, G.H. Kuo, Bioorg. Med.
Chem. Lett. 19, 2456 (2009)
12. S. Prafulla, P. Pratik, K. Prabhjot, AJRC 6, 599 (2013)
13. H.S. Kim, H.J. Gim, M. Yang, J.H. Ryu, R. Jeon, Heterocycles 71, 2131 (2007)
14. G. Dorey, B. Lockhart, P. Lestage, P. Casara, Bioorg. Med. Chem. Lett. 10, 935 (2000)
15. D.K. Dodiya, H.K. Ram, A.R. Trivedi, V.H. Shah, J. Serb. Chem. Soc. 76(6), 823 (2011)
16. H.M. Faidallah, A.A. Saqer, K.A. Alamry, K.A. Khan, A.M. Asiri, J. Enzyme Inhib. Med. Chem.
29(3), 367 (2014)
17. H.M.F. Madkour, M.A.E.M. El-Hashash, M.S. Salem, A.O.A. Mahmoud, Y.M.A.S. Al-Qahraman,
J. Heterocyclic Chem. (2017). https://doi.org/10.1002/jhet.3046
18. M.S. Salem, M.A.M. Ali, Biol. Pharm. Bull. 39, 473 (2016)
19. M.S. Salem, M. Farhat, A.O. Errayes, H.M.F. Madkour, Chem. Pharm. Bull. 63, 866 (2015)
20. M.S. Salem, A.O. Errayes, J. Chem. Res. 40, 299 (2016)
21. M.S. Salem, S.I. Sakr, W.M. El-Senousy, H.M.F. Madkour, Arch. Pharm. Chem. Life Sci. 346, 766
(2013)
22. I.H. Eissa, A.M. El-Naggar, M.A. El-Hashash, Bioorg. Chem. 67, 43 (2016)
23. M. El-Kady, E.M.H. Abbas, M.S. Salem, A.F.M. Kassem, S.I. Abd, El-Moez. Res. Chem. Intermed.
42, 3333 (2016)
24. K. Saito, S. Kambe, A. Sakurai, H. Midorikawa, Synthesis (1981). https://doi.
org/10.1055/s-1981-29388
1 3

H. M. F. Madkour et al.
25. D.R. Anderson, N.W. Stehle, S.A. Kolodziej, E.J. Reinhard, L.F. Lee, United States Patent Applica-
tion 20040142978, July 22 (2004)
26. E.J. Reinhard, S.A. Kolodziej, D.R. Anderson, N.W. Stehle, W.F. Vernier, L.F. Lee, S.G. Hegde,
United States Patent Application 20040127519, July 1 (2004)
27. M.H. Abdel-Lattif, M.I. Kobeasy, ShH Abdel-Hafez, Int. J. Basic Appl. Sci. 3(4), 433 (2014)
28. Y.M. Al-Kahraman, H.M.F. Madkour, D. Ali, M. Yasinzai, Molecules 15, 660 (2010)
29. G.S. Singh, Y.M.S.A. Al-Kahraman, D. Mpadi, M. Yasinzai, Bioorg. Med. Chem. Lett. 22, 5704
(2012)
30. G.S. Singh, Y.M.S.A. Al-Kahraman, D. Mpadi, M. Yasinzai, Med. Chem. 10, 382 (2014)
1 3