Synthesis, characterization and cytotoxic activity of some new 1,2,3-triazole, oxadiazole and Aza- β-lactam Derivatives

Article abstract of DOI:10.13005/ojc/340516

A series of 1,2,3-triazole, oxadiazole and aza-β-lactam derivatives were synthesized through consecutive reaction began from o-(N-propargyl) sulfonamido benzoic acid (1a). The reaction of (1a) with absolute ethanol in the presence of concentrated H2SO4 resulted in the formation of ester derivative (2a). The product of the previous reaction was reacted with 80% hydrazine hydrate to prepare benzohydrazide derivative (3a). 1,3,4-oxadiazole compound (4a) was obtained by condensation of compound (3a) with CS2 in presence KOH. Compound (3a) react with Phenyl isocyanates to give Carboxamide derivative (5a), that Condensation either with 2,4-dimethoxybenzaldhyde and p-hydroxybenzaldehyde to prepare the Schiff bases (6a-b). The cycloaddotion of Schiff-bases (6a-b) with phenyl isocyanate gave aza-β-lactams (7a-b). Benzamide derivatives (8a-c) were prepared via the reaction of compound (1a) with aniline derivatives, such as (p-toluidine, o-nitroaniline and m-nitroaniline). In a regioselective reaction 1,4-disubstituted-1,2,3-triazole derivative (9a-j) were synthesized via the click reaction of compounds 4a,5a and (8a-c) with benzyl azide and p-bromobenzyl azide. The compounds were identified using the spectral methods shown in the work. Cytotoxic effects of some final prepared compounds were studied in one cultured cellular models (MCF7 cell line) breast cancer (at various concentrations) by MTT assay, compound (9j) showed the better cytotoxic activity among the tested compounds.

Full text of DOI:10.13005/ojc/340516

ISSN: 0970-020 X
CODEN: OJCHEG
2018, Vol. 34, No.(5):
Pg. 2350-2360
ORIENTAL JOURNAL OF CHEMISTRY
An International Open Free Access, Peer Reviewed Research Journal
www.orientjchem.org
Synthesis, Characterization and Cytotoxic Activity of some
New 1,2,3-Triazole, Oxadiazole and Aza- β-lactam Derivatives
KANY A. AbDUL qADER1*, AHMED W. NASER1, MUTHANNA S. FARHAN2
and SAbAH J. SALIH2
1Department of Chemistry, College of Science, University of Baghdad, Baghdad, Iraq.
2Department of Pharmaceutical Chemistry, College of Pharmacy, University of Baghdad, Baghdad, Iraq.
*Corresponding author E-mail: kaneeazad@yahoo.com
http://dx.doi.org/10.13005/ojc/340516
(Received: April 08, 2018; Accepted: August 10, 2018)
AbSTRACT
A series of 1,2,3-triazole, oxadiazole and aza-β-lactam derivatives were synthesized
through consecutive reaction began from o-(N-propargyl) sulfonamido benzoic acid (1a). The
reaction of (1a) with absolute ethanol in the presence of concentrated H2SO4 resulted in the
formation of ester derivative (2a). The product of the previous reaction was reacted with 80%
hydrazine hydrate to prepare benzohydrazide derivative (3a). 1,3,4-oxadiazole compound (4a)
was obtained by condensation of compound (3a) with CS2 in presence KOH. Compound (3a)
react with Phenyl isocyanates to give Carboxamide derivative (5a), that Condensation either with
2,4-dimethoxybenzaldhyde and p-hydroxybenzaldehyde to prepare the Schiff bases (6a-b). The
cycloaddotion of Schiff-bases (6a-b) with phenyl isocyanate gave aza-β-lactams (7a-b). Benzamide
derivatives (8a-c) were prepared via the reaction of compound (1a) with aniline derivatives, such as
(p-toluidine, o-nitroaniline and m-nitroaniline). In a regioselective reaction 1,4-disubstituted-1,2,3-
triazole derivative (9a-j) were synthesized via the click reaction of compounds 4a,5a and (8a-c) with
benzyl azide and p-bromobenzyl azide.The compounds were identified using the spectral methods
shown in the work.Cytotoxic effects of some final prepared compounds were studied in one cultured
cellular models (MCF7 cell line) breast cancer (at various concentrations) by MTT assay, compound
(9j) showed the better cytotoxic activity among the tested compounds.
Keywords: Oxadiazole, Aza-β-lactam, 1,2,3-Triazole, Click Chemistry, Cytotoxicity.
INTRODUCTION
has been commonly used as a privileged scaffold
for producing different novel pharmaceutical drug
such as: antitumor3, anti-cancer agents4 and anti
prostate5, furthermore, oxadiazole derivatives
which have thioamide group CNS. Its importance
lies in eliminating the poisons in much of medicine
used by human beings6. Azetidinones are one of
A wide ranging of various heterocyclic
compounds has been discovered to develop
pharmaceutically essential molecule. Among them
which have played a significant role in medical
chemistry were oxadiazoles derivatives1,2. Which
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the heterocyclic derivatives, which are utilized as
synthase for various biologically active compounds7,
as well as their recognition as antibacterial8,
anti-inflammatory9 and anti-hepatitis10. The triazole
derivatives classified as very important heterocycles
compound, over past few years they have acquired in
thermal-cycloaddition of azide-alkyne obtain
triazole13, which catalyze by Cu (I)14-18 scheme (1).
These situations describe “click” concept perfectly.
This obtained 1,4-disubstituted regioisomer of
1,2,3-triazole and facilitate reaction at lesser
temperature. In which increasing number of
applications of Click chemistry was now being
used in various researches such organic chemistry,
bioconjugation19, drug discovery20, polymers21-22, and
radiochemistry23.
interest by introduce the “click chemistry concept” 11-12
.
In which this (process) has concentrate on reaction
between high reactives partner that was providing
access to structure which easy varied. Huisgen's
Scheme 1. Huisgen’s cycloaddition to prepare 1,4-disubstituted-1,2,3-triazoles
EXPERIMENTAL METHODS
Synthesis of o-(N-Propargyl) sulfoamido
benzohydrazide (3a)25
All chemicals were purchased from Fluka,
BDH and Merck.M.p.is recorder use electrothermal
(m.p) apparataus. The FT-IR spectral data were
recorded on a Shimadzu FT-IR8400S spectro-
photometer in the Department of Chemistry, College
Ethyl-o-(N-Propargyl) sulfoamido benzoate
(2a) (0.5 gm, 0.004 mole) was dissolved in (20 ml)
absolute ethanol, (0.05 mole) of hydrazine hydrate
was added and refluxed 4 hours.After cooling, white
precipitate was formed and re-crystallized from EtOH
to obtain compound (3a).Yield 70%, m. p.78-80oC,
IR-(KBr) cm-1 :3330-3242 NHNH2, 1656-1625(C=O)
amide.1H-NMR (DMSO-d6) (δ ppm) 1.45(s, 2H, NH2),
2.98(s, 1H, CH acetylinic), 3.91(s, 2H, CH2), 5.94
(s, 1H, NH-C=O), 7.54-7.86 (m, 4H, Ar-H).
1
of Science, University of Baghdad. H-NMR and
13C-NMR spectra are recorder on central laboratory
of Isfahan University and Sharif University of
technology, 400MHz, using CDCl3 or DMSO and
tetramethylsilane (TMS) as an internal standard.
Synthesis of ethyl-o-(N-Propargyl) sulfoamido
benzoate (2a)24
Synthesis of o-(5-mercapto-1,3,4-oxadiazol-2-yl)-
N-propargyl benzene sulfonamide (4a)26
To a solution of o-(N-propargyl) sulfonamido
benzoic acid (1a) (0.5 gm, 0.004 mole) in absolute
ethanol (30 ml), was added with stirring conc.sulfuric
acid (2 ml) the reaction mixture was refluxed for 8 h,
then the mixture was concentrated and neutralized
by NaHCO3. The white precipitate that formed was
filtered and re-crystallized from ethanol to give
compound (2a).Yield 61%, m.p.(110-112oC), IR-KBr
cm-1:3274 (C-H) Acetylinic, 2125 (C C), 1737(C=O),
1056 (C-O) Ester. 1H-NMR (DMSO-d6) (δ ppm) 1.4
(s, 3H, CH3), 2.45(s, 1H, CH acetylinic), 3.95(s, 2H,
CH2), 4.55(O-CH2), 7.3.94(s, 1H, NH-C=O), 7.65-8.2
(m, 4H, Ar-H).
A mixture of Compound (3a) (0.5 gm,
0.002 mole), with (0.004 mole) carbon disulfide
and potassium hydroxide (0.2 gm, 0.003 mole) was
dissolved in (15 ml) EtOH and refluxed 7 h, then the
solvent is evaporate and water was added into the
residue until it dissolved and acidify with dilute (HCl),
the precipitate is filtered, and washing with H2O to
give compound (4a).Yield 83%, m.p 119-120oC, IR
(KBr)cm-1: 3195(N-H), 2650(S-H), 1596 C=N. 1H-
NMR (DMSO-d6) (δ ppm) 2.82(s, 1H, CH acetylinic),
3.45(s, 1H, NH-SO2), 3.8(s, 2H, CH2), 7.80-8.03
(m, 4H, Ar-H).

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SynthesisofN-Propargyl-o-[N\-sulfamidobenzoyl]
hydrazine carboxamide (5a)27
N-[2-oxo-3-phenyl-4-[(2,4-dimethoxy)phenyl-
1,3-diazetidin-1-yl]-o-[(N-proparg yl) sulfamido]
benzamide (7a)
Yield 85%, m.p. 149-150oC, IR cm-1: 3328
(N-H), 1708 (C=O) Lactam, 1649 (C=O,Amide),
1232 (C-O).
A mixture of o-(N-Propargyl) sulfoamido
benzohydrazide (3a) (0.5gm, 0.002 mole) and
Ph=C=O (0.002 mole) was refluxed in absolute
ethanol (15 ml) for 6 hours. After cooling the
formed white precipitate was filtered, dried then
re-crystallized from (1:1) EtOH and DMF, for giving
compound (5a). Produce 85%, m.p. 134-136oC, IR
cm-1: 3298(N-H), 1672(C=O). 1H-NMR :3.09 (s, 1H,
CH acetylinic), 3.91(s, 2H, CH2), 7.4-8.33 (m, 10H,
Ar-H and SO2-NH), 9.30(s, 1H, NH).
N-[2-oxo-3-phenyl-4-[(p-hydroxy)phenyl-1,3-
diazetidin-1-yl]-o-[(N-propargyl)sulfamido]
benzamide (7b)
Yield 78%, m.p 161-162 oC, IR cm-1: 3195
(N-H), 1712 (C=O) Lactam, 1649 (C=O)-Amide,
3315 (H-O).
General method to synthesis Schiff’s bases (6a-b)28
o-(N-Propargyl) sulfoamido benzohydrazide
General-method to synthesized of benzamide
derivative (8a-c)30
(3a) (0.5 gm, 0.002 mole) was dissolved In
(20 ml) absolute EtOH. Aromatic aldehydes
namely 2,4-dimethoxybenzaldehyde and
p-hydroxybenzaldehyde,(2-3) drops of glacial
(acetic acid) were added and refluxed 5 hours. The
forming precipitate after-cooling was filtered and
re-crystallized from EtOH to give compounds (6a-b).
Compound (1a) (0.5 gm, 0.002 mole),
with (0.002 mole) of aniline derivatives such as
(p-toluidine, o-nitroaniline and m-nitroaniline) in
20 ml POCl3 was refluxed 4 hours. Then the mixture
was Concentrated and poured on crushed ice with
stirring for giving a solid mass. The product was
filtered and dried to give compounds (8a-c).
o-[(N-Propargyl)sulfamoyl]-N-(p-tolyl)benzamide
(8a):
o-[(N-Propargyl)sulfamoyl]-N-(2,4-dimethoxybenzaldine)
benzamide(6a)
Yielding 80%, m.p. 99-101 oC, IR cm-1:
3276(C-H)Acetylinic, 2130 (C C), 1735(C=O),
1H-NMR:2.12(s, 3H, CH3), 2.85(s, 1H, CH acetylinic),
3.44(s,1H,NH-SO2), 4.59(s, 2H, CH2), 6.5(s,1H,
NH-C=O), 6.48-8.34(m, 8H, Ar-H ). 13C-NMR
(δ ppm): 27.46(CH3), 75-76 (C C), 121-136 (C-Ar),
158 (C=O).
Yielding 85%, m.p. 160-163oC, IR cm-1:
3130(N-H), 1614(C=N), 1207 C-O.1H-NMR (DMSO-
d6) (δ ppm): 2.05(s, 1H, CH acetylinic), 3.7(s, 2H,
CH2), 3.8(s, 6H, 2CH3-O), 5.97(s, 1H, NH-C=O),
6.54-8.46 (m, 8H, Ar-H), 9(CH=N).
o-[(N-Propargyl)sulfamoyl]-N-(p-hydroxybenzaldine)
benzamide(6b)
Yielding 73% m.p.212-214oC, IR-KBr cm-1:
3112(N-H), 1625(C=N), 3265 (OH). 1H-NMR: 2.1(s,
1H, CH acetylinic), 3.8(s, 2H, CH2), 6.04(s, 1H, NH-
C=O), 7.3-8.1(m, 8H, Ar-H), 9.1(CH=N), 10(O-H).
o-[(N-Propargyl)sulfamoyl]-N-(m-nitrophenyl)
benzamide (8b)
Yielding 76%, m.p. 90-91oC, IR cm-1:
3276(C-H) Acetylinic, 2127 (C C), 1737(C=O).
o-[(N-Propargyl)sulfamoyl]-N-(o-nitrophenyl)
benzamide (8c):
Yield 74%, m.p 96-97oC, IR cm-1: 3274
(C-H) Acetylinic, 2125(C C), 1737(C=O).
General procedure for Synthesis of (Aza-β-
lactam-derivative) (7a-b)29
A mixture of Schiff bases (7a-b) (0.5
gm, 0.002 mole) and Ph=C=O (0.002 mole) in
(15 ml) chloroform was refluxed 6 hours.The Solvent
was removed and the residue treated through a
mixture of (1:1) ethyl acetate-petroleum ether.
The resultant ppt. was filtrated then dried to give
compounds (7a-b).
Preparation of alkyl azide31
Sodium azide (0.015 mole) was added
slowly to refluxed DMF (25 ml), the reflux was
continued until all the sodium azide dissolved then
benzyl chloride and p-bromobenzyl bromide (0.0075
mole) was slowly added, the mixture then was heated

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overnight (temperature is fixed at 750C), after cooling
(25 ml) of distilled H2O was added, 25 ml of diethyl
ether was also added and the organic-layer was
extracted (the addition of diethyl ether was repeated
three times), then the combined organic layers were
dried using magnesium sulfate and evaporated
under reduced pressure.To give the colorless liquids,
n-benzyl azide 80% and p-bromobenzyl azide 83%,
IR (KBr) cm-1: 2096(N3).
(KBr) cm-1: 3409(N-H), 1708 (C=O), 1596 (N=N),
757 (C-Br). 1H-NMR: 4.80(s, 2H, CH2), 5.41(s, 2H
benzylic), 7.25-8.33(m, 15H, Ar-H and SO2-NH),
9.30 (s, 1H, NH). 13C-NMR (δ ppm): 45(NH-CH2),
60(C- benzylic), 121-138(C-Ar), 153-166(C=O).
o-[N-(1-benzyl)-1,2,3-triazol-4-yl]methylsulfamoyl
-N-(p-tolyl)benzamide(9e)
Yielding 80%, m.p.198-199oC, IR-KBr cm-1:
3452 (N-H), 1726 (C=O), 1596 (N=N).
General procedure of synthesis 1,4-disubstituted-
1,2,3-triazole derivatives (9a-j)31
o-[N-(1-(p-bromobenzyl))-1,2,3-triazol-4-yl]
methylsulfamoyl-N-(p-tolyl) benzamide (9f)
Yielding 75%, m.p. 164-165oC, IR cm-1:
A mixture of compounds 4a, 5a and (8a-c)
(0.002 mole) was slowly added with stirring to a
solution containing sodium ascorbate (0.00045
mole) and CuSO4.5H2O (0.002 mole) in (25 ml)
DMF, then p-bromobenzyl azide and benzyl azide
(0.005 mole) was added. The mixture then heated
overnight (the temperature was fixed at 75oC), after
cooling 25 ml of distilled water was added, 25 ml of
diethyl ether was also added to the mixture and the
organic-layer was extracted (the addition of diethyl
ether was repeated three times), then the combined
organic-layers were dried over magnesium sulfate,
the forming ppt. was filtered and dried to give
compounds (9a-j).
3422(N-H), 1724(C=O), 1595(N=N), 586(C-Br).
1H-NMR: 2.21(s, 3H, CH3), 5(s, 2H, N-CH2), 5.48
(s, 2H, benzylic), 7.25-8.33(m, 13H, Ar-H and SO2-
NH). 13C-NMR (δ ppm): 28(CH3), 33(NH-CH2), 52
(C-benzylic),121-136(C-Ar), 158(C=O).
o-[N-(1-benzyl)-1,2,3-triazol-4-yl]methylsulfamoyl
-N-(m-nitrophenyl) benzamide (9g)
The product 70%, m.p.180-181oC, IR cm-1:
3419(N-H), 1731(C=O), 1595(N=N), (1535) asym.
(1336) sym. NO2.
o-[N-(1-(p-bromobenzyl))-1,2,3-triazol-4-yl]methyl
sulfamoyl-N-(m-nitrophenyl)benzamide (9h):
The product 72%, m.p.150-151oC, IR cm-1:
o-(5-mercapto-1,3,4-oxadiazol-2-yl)-N-(1-benzyl-
1,2,3-triazol-4-yl)methyl benzene sulfonamide (9a)
The product 80%, m.p. 212-215oC, IR
cm-1: 3338(N-H), 1618(N=N), 1164(C=S). 1H-NMR:
4.99 (s, 2H, CH2), 5.58(s, 2H, benzylic), 7.25-8.33
(m, 13H, Ar-H and SO2-NH),11.77(s, 1H, SH).
13C-NMR (δ ppm): 31(NH-CH2), 52(C-benzylic),
127-133 (C-Ar).
3390(N-H), 1722 (C=O), 1595(N=N), (1539) asym.
1
(1325) sym. NO2. H-NMR:4.99 (s, 2H, N-CH2),
5.58(s, 2H,benzylic), 7.25-8.33 (m, 13H, Ar-H
and SO2-NH). 13C-NMR (δ ppm): 33(NH-CH2), 52
(C-benzylic), 121-136 (C-Ar), 158(C=O).
o-(5-mercapto-1,3,4-oxadiazol-2-yl)-N-(1-(p-
bromobenzyl-1,2,3-triazol-4-yl)) methyl benzene
sulfonamide (9b)
o-[N-(1-benzyl)-1,2,3-triazol-4-yl]methylsulfamoyl-N-
(o-nitrophenyl) benzamide (9i)
The product 70%, m.p. 188-189oC, IR cm-1:
The product 66%, m.p.175-176oC, IR (KBr)
cm-1: 3423(N-H), 1564 (N=N), 1161(C=S).
3440(N-H), 1726(C=O), 1627(N=N), (1460) (1330)
1
NO2 (asym.) (sym.). H-NMR: 4.99(s, 2H, N-CH2).
5.58(s, 2H, benzylic), 7.25-8.33(m, 13H, Ar-H
and SO2-NH). 13C-NMR (δ ppm): 33(NH-CH2), 52
(C-benzylic), 121-136 (C-Ar), 158(C=O).
o-[(N-1-benzyl-1,2,3-triazol-4-yl)]methyl sulfamido-
N-phenyl benzoyl hydrazine carbamide (9c)
The product 65%, m.p.228-231oC, IR (KBr)
cm-1: 3471(N-H), 1720(C=O), 1562 (N=N).
o-[N-(1-(p-bromobenzyl))-1,2,3-triazol-4-yl]
methylsulfamoyl-N-(o-nitrophenyl) benzamide (9j)
The product 68%, m.p.158-159oC, IR cm-1:
3407(N-H), 1722(C=O), 1593(N=N), (1560) (1325)
NO2 (asym.) (sym.).
o-[(N-(1-(p-bromobenzyl))-1,2,3-triazol-4-yl)]
methylsulfamido-N-phenyl benzoyl hydrazine
carbamide (9d)
The product 78%, m.p. 180-183oC, IR

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qADER et al., Orient. J. Chem., Vol. 34(5), 2350-2360 (2018)
In vitro Cell viability Assay (MTT)32
H2SO4 gave compound (2a) that have been reacted
with 80% hydrazine hydrate to give o-(N-propargyl)
sulfonamido benzohydrazide (3a). The absence
of (C=O ester) stretching-band at (1737) cm-1 and
the presence of new stretching-bands, at (3242-
3330) cm-1 and 1656 cm-1 that due to (NH-NH2)
and (C=O amide) respectively are attributed to
the formation of benzohydrazide derivative (3a),
The cytoxicity profiles were estimated by
using “3-[4,5-dimethyl-thiazol-2-yl]- 2,5-diphenyl-
tetrazolium bromide”(MTT) microculture, tetrazolium
viability-method. To prepare stock solution we
dissolve the compounds in DMSO and sequential
dilution (12.5 μg/ml–200 μg/ml) were prepared
through dissolving stock-solutions in cualture-
cellular modelas (MCF-7 cell line) breast-cancer.
At the exact time in which after compounds (4a,
6a and 8f) treatment, MTT (5 mg/mL) was added
in each wells and incubation of plate are 4 hours.
After removing the media, DMSO is add into each
well for solubilized formazan-crystals. The same
method is returned but using WRL-68 normal cell
(liver cell) as negative control. Absorbance was
measured at wavelength (575 nm) using (Hidex
Chamealon platereader). Perceantage of cellular-
viabilities were calculated with suitable control take
into account. The concentration that inhibition 50%
of cell-growth (IC50 value) is determined. All-tests
are executed in triplicate. Percentage viability of
cells exposed to various treatments was obtained
as follows: cell Viability %=( Absorbance treated
sample/ Absorbance of non-treated sample) ×100
(Non-treated cultures in all experiments contained
the medium only).
1
while H-NMR spectrum Fig. (1) showed absence
of signals 1.4ppm (CH3), 4.55 ppm(O-CH2), and
appearance of signals at 1.45 ppm (NH2), 5.94 ppm
(NH-C=O) ppm. Cyclization of (3a) with (CS2) in
presence (KOH) give 1,3,4-oxadiazole compound
(4a) (scheme 2). Absence of stretching bands at
(3242-3330) cm-1 for (NH-NH2) and (1656) cm-1 for
(C=O amide) and presence weak stretching band of
SH (2650) cm-1 and stretching band (C=N) (1596)
cm-1 is attributed to the formation compound (4a),
while 1H-NMR of compound (4a) Fig. (2) display the
following characteristic signals δ(ppm): 2.82(s, 1H,
CH acetylinic), 3.8 (s, 2H, CH2), 7.8-8.03(m, 4H,
Ar-H), 8.2(s, 1H, NH-SO2).The reaction of compound
(3a) with phenyl isocyanate to give compound (5a).
The product was identified by FT.IR spectrum which
shows absence of stretching band of (NH-NH2) at
(3242- 3330) cm-1 and existence of new absorption
bands due to (NH) at (3220) cm-1 and (C=O) at (1672)
cm-1. Schiff-bases (6a-b) were synthesized by
condensationofhydrazinederivative(3a)withvarious
aromaticaldehydes(2,4-dimethoxybenzaldehydeand
p-hydroxybenzaldehyde) with few drops of (glacial-
acetic acid).The absence of (NH2) stretching bands
RESULTS AND DISCUSSION
The synthesized of Oxadiazole, Aza-β-
lactam and 1,2,3-triazole derivatives were achieved
by starting from compound (1a) that react with
absolute ethanol, in the presence concentrated
Fig. 1. 1H-NMR spectrum of compound (3a)

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Fig. 2. 1H-NMR spectrum of compound (4a)
at (3242-3330) cm-1 and appearance (C=N) stretching
band at (1596-1602) cm-1 indicate the formation
(8a-c) were synthesized by condensation compound
(2a) with aniline derivatives such as (p-toluidine,
o-nitroaniline and m-nitroaniline) in presence POCl3.
The absence of absorption band of (O-H) at (3309)
cm-1, and appearance absorp. band of (C=O amide)
at (1735-1737) cm-1 gave good evidence for formation.
While 1H-NMR spectrum of compound 8a Fig. (3)
showed appearance of signals at 2.85 ppm (CH
acetylinic), 6.5 ppm (NH-C=O), the 13C-NMR of
compound 8a Fig. (4) display 27.46 (CH3), 75-76 (C
C), 121-136 (C-Ar), 158 (C=O).
1
of Schiff-bases, while H-NMR spectrum showed
singlet signal for (CH=N) at 9.1 ppm. Moreover, The
cyclization of (6a-b) with phenyl isocyanate via [2+2]
cycloaddition reaction gave the corresponding “1,3-
diazetidine-2-one (Aza-β-lactam)” (7a-b) derivatives.
The disappearance of stretching band of (CH=N-) at
(1614-1625) cm-1 and appearance stretching band of
(C=O aza-β-lactam) at (1708-1712) cm-1 were utilized
to confirm the compounds. Benzamide derivatives
Fig. 3. 1H-NMR spectrum of compound (8a)
cm-1 for acetylenic C-H, (2125-2127) cm-1 for C C
and 2096 cm-1 for azide group and appearance of
new band for (N=N) at (1626-1562). While 1H-NMR
and 13C-NMR spectra of compounds (9a), (9f), (9h)
and (9i) exhibit the absence of singlet signal at (2.8)
1,4-disubsituted-1,2,3-triazole derivatives
(9a-j) (scheme 3) were prepared under click
conditions by refluxing compounds 4a, 5a and
(8a-c) with (benzyl and p-bromobenzyl) azide.
Disappearance of absorption bands at (3274-3298)

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ppm due to (C-H) acetylenic Fig. (5),(6),(8),(10) and
disappearance of the signal at (75-76) ppm due to (C
C) Fig.(7),(9),(11) is good evidence for the formation
of the 1,2,3-triazole derivatives.
Fig. 4. 13C-NMR spectrum of compound (8a)
Fig. 5. 1H-NMR spectrum of compound (9a)
Fig. 6. 1H-NMR spectrum of compound (9f)

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Fig. 7. 13C-NMR spectrum of compound (9f)
Fig. 8. 1H-NMR spectrum of compound (9h)
Fig. 9. 13C-NMR spectrum of compound (9h)

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Fig. 10. 1H-NMR spectrum of compound (9i)
Fig. 11. 13C-NMR spectrum of compound (9i)
In-vitro cytotoxic activity
The results of cytotoxic activity of
(12.5-200 μg/ml) the best inhibition was at 100 μg/ml
by compound (12f) exhibited 71.66% of cancer cell
death, with IC50 value 56.19 μg/ml while exhibited
9.61% of normal cell death. As we comparison with
another studying of anticancer potential33 we find
the best inhibition exhibited 51.4% at 100 μg/ml on
MCF-7 cell line compared to 25 μg/ml doxorubicin
as positive control so they didn’t use normal cells.
compounds (4a, 6a and 9j) on MCF7 cancer cell
were represented in Table 1 and Fig. (12, 13 and
14) compared to normal cell line WRL-68 (liver cell)
as negative control. The results showed that when
we treated (MCF-7) cell with different concentrations
Table 1: the anticancer activity of compounds 4a, 6a and 9j on MCF7 cell line by MTT method
Concentrations of comp. (µg/ml) (Mean SD)
Cell lines
MCF-7
WRL-68
Comp. no. 200
100
40.81
7.73
52.49
9.80
50
25
0.16
4.85
_
12.5
2.69
2.74
_
200
35.77
7.37
41.83
12.46
44.33
23.82
100
7.51
4.45
_
50
25
12.5
0.69
2.49
0.67
4.75
2.46
18.36
4a
6a
9j
66.09
8.21
67.01
1.67
84
6.58
6.45
15.36
7.59
52.47
5.14
1.19
3.03
1.51
2.68
8.37
7.29
2.57
0.89
0.42
4.02
0.74
6.65
71.66
4.79
14.7
3.57
3.35
4.18
9.61
39
8.21

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qADER et al., Orient. J. Chem., Vol. 34(5), 2350-2360 (2018)
Scheme 2. Route of synthesized compounds (2a-5a),(6a-b),(7a-b) and (8a-c)
Scheme 3. Route of Synthesized compounds (9a-9j) via click reaction
Fig. 12. The cytotoxic activity represented by viability rate
Fig. 13. The cytotoxic activity represented by viability rate
of comp. (4a)
of comp. (6a)

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qADER et al., Orient. J. Chem., Vol. 34(5), 2350-2360 (2018)
chemistry”. The studying of cytotoxicity activity on
some final prepared compounds (4a, 6a and 9j)
showed that tested compounds have a promising
significant (p≤0.05) cytotoxic activity. Compound 9j
showed the best cytotoxic activity that has strong
cell-growth inhibition with IC50 56.19 μg/ml.
ACKNOWLEDGMENT
Fig. 14. The cytotoxic activity represented by viability rate
As the authors of this work, we would love
to express our ample thankfulness and gratitude to
the Department of Chemistry, College of Science,
University of Baghdad and College of Pharmacy,
for their magnificent support and providing us with
facilities to conduct this research on all accounts.
of comp. (9j)
CONCLUSION
Some new oxadiazole, Aza-β-lactam
derivatives were synthesized, and to obtained
“1,4-disubstituted-1,2,3-triazole through click-
REFERENCES
1.
2.
3.
4.
5.
6.
7.
Raut, A.B.; Matto, M. R.; Acta. Chim. Solv.,
2008, 55,448.
Babak, K.; Leila, M.; Tetrahedron lett., 2011,
52,6424-6426.
Noha, I.Z.; Fabio, S .; Stefamo, F.; European.
J. Med. Chem., 2010, 45, 4523.
19.
20.
Wang, q.; Chan, T. R.; Hilgraf, R.; Fokin, V.V.;
Sharpless, K.B.; Finn M.G.; J. Am. Chem.
Soc., 2003,125, 3192.
Manetsch, R.; Krasinski, A.; Radic, Z.;
Raushel, J.; Tylor, P.; Sharpless, K.B.; Kolb
H.C.; J. Am. Chem. Soc., 2004,126,12809.
Helms, B.;Mynar, J.L.;Hawker, C.J.;Fréchet,
J.M.; J. Am. Chem. Soc., 2004, 126, 15020.
Karim, A. M.; Park, J. S.; DSSCs. Macromol
Chem Phys., 2008, 209, 1967.
Schirrmacher, R.;Wangler, C.;Schirrmacher,
E.; Mini-Rev Org Chem., 2007, 4, 317.
Hussein, F.; Hello, K. M.; J. of Chem., 2002,
26(1), 35-41.
Abdulla, A. F.; MSc. Thesis, University of
Baghdad, College of Science, 2015.
Hasan, A.;Thomas, N.F.;Gapil, S.;Molecules.,
2011, 16(2), 1297-1309.
Dali P.; Gautum, P.; Angpla, K.C.; European.
J. Med. Chem., 2011, 46, 3085-3092.
Gopal,L.K.;Jasmine,K.;Varnm,K.;Bio.Organic.
Med. Chem let., 2012, 22,1912-1916.
John, K.A.; Veeramani, V.P.; Sharmila, N. S.;
Tetrahedron lett., 2009, 65, 9989-9996.
Aoyama, Y.; Uenaka, M.; Konoike, T.;
Nakayima, M.; Bioorganic and Medicinal
chemistry letters., 2001, 11, 1691.
James, A.H.; Glenn, S.T.; Robert, T.; Roger,
M.E.; J. Antimicr. Chemoth., 2007, 4, 923.
Srivastava, S.K.;Srivastava, S.L.;Srivastava,
S.D.; Indian J. Chem., 2000, 39, 464.
Vaishnav, P.; Demain, A.; Biotechnol. Adv.,
2010, 7, 50.
Kolb, H.C.;Finn, M.G.;Sharpless, K.B.;Angew.
Chem. Int. Ed., 2001, 40, 2 0 0 4 - 2 0 2 1 .
Kolb, H. C.; Sharpless, K. B.; Drug Discov.
Today., 2003, 8, 1128-1137.
Moses, J. E.; Moorhouse, A. D.; Chem. Soc.
Rev., 2007, 36, 1249-1262.
Tornøe, C.W.;Christensen, C.;J.Org.Chem.,
2002, 67, 3057-3064.
Rostovtsev, V. V.; Green, L. G.; Fokin, V.V.;
Sharpless, K.B.;Angew.Chem.Int.Ed., 2002,
41, 2596-2599.
Hiemstra, V. D.; Maarseveen, H. van; Eur. J.
Org. Chem., 2006, 51-68.
Wu,P.;Fokin,V.V.;Aldrichim.Acta., 2007, 40, 7-17.
Meldal, M.;Tornøe, C.W.;Chem. Rev., 2008,
108, 2952-3015.
21.
22.
23.
24.
25.
26.
27.
28.
29.
8.
9.
El–Tamaty, E.S.;Abdel– Fattah, M.E..;Indian
J. Chem., 1996, 35, 1067.
10.
11.
12.
13.
14.
15.
Naser, A. W.; Iraqi National Journal of
Chemistry., 2013, 50, 199.
Furniss, B.; Hannaford, A. H.; Smith, P.;
Tatchell, A.; Vogel’s Text book of practical
organic chemistry, 5th Ed., Addison Wesley
Longman, 1998, 1077.
Issac, Y. A.; Mohamed, S. K.; Eissa, A. M.;
Tantawya, A. H.; EL-Sawya, A. A.; Journal
of Chemical and Pharmaceutical Research.,
2012, 4(5), 2744-2750.
Shneshil, M. K.; Ph.D. Thesis, University of
Babylon, College of Science, 2016.
Denizot, F.; Lang, R.; J. of Immunological
Methods., 1996, 89(2), 271–277.
30.
31.
32.
33.
16.
17.
18.
Alshanon, A. F. ; Firas, H.; Abdul hameed, A.
and Alsaffar, A. Z.; International Journal of
Pharma Sciences., 2015, 5(1), 904-910.