Synthesis and Antimicrobial Activity of Methyl 2-(2-(2-Arylquinazolin-4-yl)sulfanyl)acetylamino Alkanoates

Article abstract of DOI:10.1002/jhet.3348

A series of methyl 2-(2-(2-arylquinazolin-4-yl)sulfanyl)acetylamino alkanoates have been developed on the basis of the S-chemoselective reaction of 2-arylquinazolin-4(3H)-thione with ethyl chloroacetate and N,N′-dicyclohexylcarbodiimide coupling method with amino acid ester hydrochloride. The precursor 2-arylquinazolin-4(3H)-thione was prepared by a new thiation method from 2-arylquinazolin-4(3H)-one by a two-step reaction that includes chlorination and then the reaction with N-cyclohexyldithiocarbamate cyclohexyl ammonium salt. The antimicrobial activity of the synthesized compounds was tested in vitro via paper-disc agar-plate method against two bacterial strains Gram-positive bacteria Staphylococcus aureus and Gram-negative bacteria Escherichia coli and a pathogenic yeast Candida albicans. Most synthesized compounds showed remarkable antibacterial activity against E.?coli overpassing the standard reference antibiotics applied: tetracycline, erythromycin, and novobiocin. On the other hand, most synthesized compounds gave moderate antifungal activity against pathogenic yeast C.?albicans.

Full text of DOI:10.1002/jhet.3348

Month 2018
Synthesis and Antimicrobial Activity of Methyl 2-(2-(2-Arylquinazolin-
4-yl)sulfanyl)acetylamino Alkanoates
*
M. I. Megahed and W. Fathalla
Physics and Mathematical Engineering Department, Faculty of Engineering, Port Said University, Port Said, Egypt
*E-mail: walid3369@yahoo.com
Received June 25, 2018
DOI 10.1002/jhet.3348
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
A series of methyl 2-(2-(2-arylquinazolin-4-yl)sulfanyl)acetylamino alkanoates have been developed on
the basis of the S-chemoselective reaction of 2-arylquinazolin-4(3H)-thione with ethyl chloroacetate and
N,N0-dicyclohexylcarbodiimide coupling method with amino acid ester hydrochloride. The precursor 2-
arylquinazolin-4(3H)-thione was prepared by a new thiation method from 2-arylquinazolin-4(3H)-one by
a two-step reaction that includes chlorination and then the reaction with N-cyclohexyldithiocarbamate
cyclohexyl ammonium salt. The antimicrobial activity of the synthesized compounds was tested in vitro
via paper-disc agar-plate method against two bacterial strains Gram-positive bacteria Staphylococcus aureus
and Gram-negative bacteria Escherichia coli and a pathogenic yeast Candida albicans. Most synthesized
compounds showed remarkable antibacterial activity against E. coli overpassing the standard reference anti-
biotics applied: tetracycline, erythromycin, and novobiocin. On the other hand, most synthesized compounds
gave moderate antifungal activity against pathogenic yeast C. albicans.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
it interesting to prepare a number of methyl 2-(2-
(2-arylquinazolin-4-yl)sulfanyl)acetylamino alkanoates
Quinazolines [1] constitute an important class of
heterocyclic compounds especially in medicinal chemistry.
These compounds possess a wide range of antimicrobial
[2–5], antimalarial [6], analgesic [7], anti-inflammatory
[8], antiviral [9], and antitumor activities [10,11].
7–8(a–f) and evaluate their antimicrobial activities.
RESULTS AND DISCUSSION
The chemoselective reactions of heterocyclic thioamides
always attracted our research group [12–14]. Earlier we
eported the chemoselective S-alkylation and N-alkylation
of the model compound 4-methyl-1-thioxo-1,2,4,5-
2-Arylquinazolin-4(3H)-ones 1a–b are excellent
precursors for the preparation of our target substrate
2-arylquinazolin-4(3H)-thiones
4a–b
by
thiation
procedures. These quinazolinone derivatives 1a–b
were prepared by multistep reactions starting from
anthranilic acid [18]. The transformation of heterocyclic
amides into thioamides is an important task in organic
synthesis. Earlier reports for this type of O/S conversions
were achieved by several thiating reagents such as
tetrahydro[1,2,4]triazolo[4,3-a]quinazolin-5-one
with
different electrophiles. These results were supported by
quantum-chemical calculations [12,13].
Non-proteinogenic amino acids are major component
in a number of drugs including β-lactam antibiotics,
glutamate antagonists, and antiviral [15–17].
Lawesson’s
reagent
(2,4-bis(4-methoxyphenyl)-1,3-
The attachment of new quinazoline ring to proteinogenic
or non-proteinogenic amino acid esters might provide
structures with interesting conformation, stability, and
biological activity. A strong need still remains to construct
structures of quinazoline derivatives linked to amino acid
residues by a spacer using simple, mild, selective, and
efficient synthetic methods. In continuation of our interest
in the chemistry of heterocyclic thioamides, we found
dithia-2,4-diphosphetane-2,4-disulfide) [19–21], Berzelius
reagent [22–24] (P4S10), and phosphorus pentasulfide [25]
in dry toluene, xylene, or pyridine under reflux condition.
Thus, the reaction of 2-arylquinazolin-4(3H)-one 1a–b
with phosphorus pentasulfide in boiling xylene afforded
2-arylquinazolin-4(3H)-thione 4a–b in poor yield 14%
(method C), with bad smell during the workup procedure.
Our alternative method for the preparation of 2-
© 2018 Wiley Periodicals, Inc.

M. I. Megahed and W. Fathalla
Vol 000
arylquinazolin-4(3H)-thione 4a–b was achieved by a two-
step procedure: chlorination of 2-arylquinazolin-4(3H)-
one 1a–b, followed by thiation via reaction with thiourea
in the presence of strong base to afford the thione
derivative 5a–b in low yield (35%) and bad smell during
workup (method B; Scheme 1) [26].
chloroacetate in the presence of triethylamine in ethanol
gave the chemoselective S-substituted quinazoline ester
derivatives 5a–b in good yield (Scheme 1) [12–14].
(2-Arylquinazolin-4-ylsulfan-yl)acetic acid 6a–b in pure
state and in good yields was successfully achieved by
saponification of esters 5a–b with KOH in methanol
water mixture with stirring at room temperature for 4 h
(Scheme 1).
Our successful method to introduce a peptide bond at the
S-atom connected to the quinazoline ring moiety was
efficiently carried out with the key substrate carboxylic
acid derivatives 6a–b via N,N0-dicyclohexylcarbodiimide
(DCC) coupling method. The DCC coupling method is
one of the major tools employed to introduce peptide
bonds by the reaction of carboxylic acid with amino acid
methyl ester [31,32]. Hydroxybenzotriazole (HOBt) is
widely used as an additive to decrease racemization in
the carbodiimide peptide coupling and to enhance the
percentage yield [32].
A number of methods have been applied for the
preparation of aryl and alkyl isothiocyanates from
dithiocarbamates using the appropriate desulfurylating
reagents. Among these desulfurylating reagents of special
interest is the use of chloroheterocycles such as 2-chloro-
1-methylpyridinium iodide [27], cyanuric chloride [28],
and 2,4-dichloro-5-nitropyrimidine [29]. The reaction
starts by the reaction of alkyl dithiocarbamate potassium
salt or triethyl ammonium salt with the chloroheterocycles
to principally give the in situ generated heterocyclic
substituted carbamodithioate, which was subsequently
converted to the mercapto heterocycles as by-products and
the desired isothiocyanate derivatives in high yield under
strong basic condition (NaOH) [28], weak base (NET3)
[27], or in the absence of a base [29]. We found it
interesting to maximize the benefit of these findings in the
synthesis of quinazoline-4(3H)-thione 5a,b from the
corresponding quinazoline-4(3H)-one 1a,b.
Treatment of carboxylic acid 6a–b with amino acid ester
hydrochlorides in the presence of triethylamine and
coupling reagents DCC and HOBt afforded S-quinazoline
amino acid esters 7–8(a–f) in good yield (Scheme 2 and
Table 1).
This method started by a first step chlorination
of the corresponding quinazoline-4(3H)-one 1a–b to
afford chloroquinazolines 2a–b. The second step
involves heating the chloroquinazolines 2a–b with N-
cyclohexyldithiocarbamate cyclohexyl ammonium salt 3
in chloroform for 12 h at 61°C to afford quinazolinethione
4a–b in excellent yields (Scheme 1) [30].
The chemical confirmation of this new thiation
procedure was carried out by structure modification of the
resultant thione derivatives 4a–b to give a number of
biologically promising compounds. Structure modification
of the model compounds 4a–b could be simply achieved
by chemoselective alkylation reactions with electrophiles.
Thus, the reaction of quinazolines 4a–b with ethyl
The 1H NMR spectrum of compound 7a in CDCl3
showed multiplet signals ranging between 8.63 and
7.54 ppm corresponding to nine aromatic protons, broad
singlet signal at 7.41 ppm corresponding to NH proton of
the peptide bond, singlet signal at 4.23 ppm for SCH2
group, doublet signal at 4.02 ppm for NCH2 group, and
singlet signal at 3.57 ppm for three protons of OCH3.
The 13C NMR spectrum of 7a showed signals for
CO group appeared at 171.9 and 169.6 ppm, signals
for C–Ar appeared at 168.6, 158.9, 149.2, 137.4, 134.3,
130.9, 129.2, 128.7, 128.5, 127.2, 123.7, and 122.2 ppm,
signal at 52.2 ppm for OCH3 group, signal at
41.6 ppm for NHCH2 group, and signal at 32.6 ppm for
SCH2 group.
Scheme 1. Synthesis of 2-((2-arylquinazolin-4-yl)thio)acetic acid 6a–b.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Synthesis and Antimicrobial Activity of Methyl 2-(2-(2-Arylquinazolin-4-yl)
sulfanyl)acetylamino Alkanoates
Scheme 2. Synthesis of methyl 2-(2-(2-arylquinazolin-4-yl)sulfanyl)acetylamino alkanoates 7–8(a–f).
Table 1
Table 2
Structures of methyl 2-(2-(2-arylquinazolin-4-yl)sulfanyl)acetylamino
Samples (30 μg each) were analyzed using “disc diffusion method.”
alkanoates 7–8(a–f).
Antifungal
activity
No.
R1
n
R2
Abr.
Antibacterial activity
Zone of
inhibition
(mm)
7a
7b
7c
7d
7e
7f
8a
8b
8c
8d
8e
8f
H
H
H
H
H
0
1
2
0
0
0
0
1
2
0
0
0
H
H
H
CH3
Gly
β-Ala
γ-Abu
L-Ala
L-Val
L-Leu
Gly
β-Ala
γ-Abu
L-Ala
L-Val
L-Leu
Zone of inhibition (mm)
Escherichia
coli
Staphylococcus
Candida
albicans
CH (CH3)2
CH2CH(CH3)2
Code no.
aureus
H
Control
4a
4b
5a
5b
6a
6b
7a
7b
7c
7d
7e
7f
8a
8b
8c
-ve
0.7
0.7
1.7
0.7
1.5
1.9
0.9
0.9
0.7
1.0
0.9
0.7
0.6
0.6
0.9
0.8
-ve
0.6
0.7
-ve
-ve
1.0
0.8
2.5
1.1
2.9
1.9
0.8
-ve
-ve
-ve
-ve
1.2
0.8
-ve
-ve
-ve
-ve
-ve
0.6
-ve
-ve
1.0
0.8
1.9
0.7
1.6
1.5
0.9
0.6
0.6
0.9
-ve
0.8
0.7
0.6
0.8
0.8
-ve
0.7
1.2
2
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
H
H
H
CH3
CH (CH3)2
CH2CH(CH3)2
Antibacterial and antifungal activities. The compounds
quinazolinthione 4a–b, ester 5a–b, acid 6a–b, and
methyl 2-(2-(2-arylquinazolin-4-yl)sulfanyl)acetylamino
alkanoates 7–8(a–f) in addition to the reference
tetracycline, erythromycin, and novobiocin were tested
in vitro against two reference bacterial strains (Escherichia
coli NCMB 11943 and Staphylococcus aureus NCMB
6571) and a pathogenic yeast Candida albicans. The
method applied is paper-disc agar-plate method [33],
using two concentrations 30 and 15 μg per disc. The
plates were incubated at 37°C for 24 h for antibacterial
evaluation and at 37°C for 48 h for antifungal evaluation.
The antimicrobial activity was evaluated by measuring the
diameter of the inhibition zone (IZ) around the disc in
millimeter as shown (Tables 2 and 3).
8d
8e
8f
Tetracycline
Novobiocin
-ve, no inhibition zone was observed.
for the starting ester derivative 5a and carboxylic acid
derivatives 6a–b with IZ ranging 1.5–1.9 mm.
From the results listed in Tables 2 and 3, we can
conclude the following:
3. Best antibacterial activity against Gram-negative bac-
teria E. coli for the amino acid ester derivatives 7–8(a–
f) was observed for 7a–b and 7d–e (R1 = H, amino acid
residue Gly, β-Ala, L-Ala, and L-Val, respectively), IZ
1.0–0.9 mm. On the other hand, compounds 9c–d
(R1 = OCH3, amino acid residue γ-Aba and L-Ala)
showed IZ 0.9 and 0.8 mm, respectively.
1. Table 2 shows general screening for all compounds and
reference antibiotics: tetracycline and novobiocin with
concentrations of 30 μg toward the microorganisms—
Gram-positive bacteria S. aureus, Gram-negative bacte-
ria E. coli, and pathogenic yeast C. albicans.
2. Almost all compounds tested showed high activity
against Gram-negative bacteria E. coli (IZ ranging from
0.6 to 1.9 mm) overpassing the standard reference anti-
biotics applied—tetracycline (IZ = 0.7 mm) and novo-
biocin (no IZ). Remarkable antibacterial activity
against Gram-negative bacteria E. coli was observed
4. The starting quinazoline thione 4a–b, esters 5a–b, and
acids 6a–b showed maximum activity against Gram-
positive bacteria S. aureus (IZ ranging from 0.8 to
2.9 mm) overpassing the standard reference antibiotics
applied—tetracycline (IZ = 0.6 mm) and novobiocin
(no IZ). Exceptionally, amino acid esters 7a, 7f, 8a,
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M. I. Megahed and W. Fathalla
Vol 000
Table 3
Samples (15 μg each) were analyzed using “disc diffusion method.”
Antibacterial activity
Antifungal activity
Zone of inhibition (mm)
Zone of inhibition (mm)
Code no.
Escherichia coli
Staphylococcus aureus
Candida albicans
Control
5a
6a
6b
-ve
2.0
1.8
1.8
-ve
-ve
1.9
1.5
1.5
-ve
-ve
2.2
2.3
1.9
2
Erythromycin
-ve, no inhibition zone was observed.
and 8f (R1 = H, Gly and L-Leu; R1 = OCH3, Gly and
L-Leu) gave promising activity against Gram-positive
bacteria S. aureus (IZ 0.8–1.2 mm) overpassing the
standard reference tetracycline.
ammonium salt 3. This compound was used to prepare a
series of methyl 2-(2-(2-arylquinazolin-4-yl)sulfanyl)
acetylamino alkanoates 7–8(a–f) on the basis of
chemoselective S-alkylation reaction of heterocyclic
thioamides. 2-Arylquinazolin-4(3H)-thione 4a–b react
with ethyl chloroacetate to give the S-substituted
quinazoline 5a–b, followed by hydrolysis to give the
carboxylic acids 6a–b. The carboxylic acid derivatives
reacted with a series of amino acid ester hydrochloride in
the presence of DCC, HOBt, and triethylamine to give
the desired products 7–8(a–f).
The antimicrobial activity of the synthesized compounds
was tested in vitro via paper-disc agar-plate method against
two bacterial strains Gram-positive bacteria S. aureus
and Gram-negative bacteria E. coli and a pathogenic
yeast C. albicans. Most synthesized compounds showed
remarkable antibacterial activity against E. coli
overpassing the standard reference antibiotics applied:
tetracycline, erythromycin, and novobiocin. On the
other hand, most synthesized compounds gave moderate
antifungal activity against pathogenic yeast C. albicans.
Finally, the tested compounds gave an equivocal
antibacterial activity toward Gram-positive bacteria
S. aureus with some few examples exceeding the activity
of the standard reference antibiotics.
5. Almost all compounds tested showed moderate activity
against pathogenic yeast C. albicans (IZ ranging from
0.6 to 1.9 mm). The IZ of the standard reference antibi-
otics applied—tetracycline (IZ = 1.2 mm) and novobio-
cin (IZ = 2.0 mm)—overpasses the antifungal activity
of the tested compounds.
6. Maximum antifungal activity against pathogenic yeast
C. albicans was observed for the ester derivative 5a
(R1 = H) and carboxic acids 6a (R1 = H) and 6b
(R1 = OCH3) showing IZ 1.9, 1.6, and 1.5 mm,
respectively.
7. Maximum antimicrobial activity of all screened com-
pounds toward all three microorganisms Gram-negative
bacteria E. coli and pathogenic yeast C. albicans was
observed for the starting ester derivative 5a and carbox-
ylic acid derivatives 6a–b.
8. Table 3 shows antimicrobial testing for compounds es-
ter 5a and acid derivatives 6a–b and reference antibiotic
erythromycin with concentrations of (15 μg) toward the
microorganisms—Gram-positive bacteria S. aureus,
Gram-negative bacteria E. coli, and pathogenic yeast
C. albicans. The starting quinazoline esters 5a and acids
6a–b showed maximum activity against all three micro-
organisms Gram-positive bacteria S. aureus, Gram-
negative bacteria E. coli, and pathogenic yeast
C. albicans overpassing the standard reference antibi-
otic erythromycin.
EXPERIMENTAL
General. The boiling point range of the petroleum ether
used was 40–60°C. Thin-layer chromatography was carried
out on silica gel 60 F254 plastic plates (layer thickness
0.2 mm; E. Merck). The spots on thin-layer plates were
detected by UV lamp. Melting points were determined on
a Buchi 510 melting point apparatus, and the values are
CONCLUSIONS
1
uncorrected. H and 13C NMR spectra were recorded at
The precursor 2-arylquinazolin-4(3H)-thione 4a–b was
prepared by a new thiation method designed in our
laboratory from 2-arylquinazolin-4(3H)-one 1a–b by a
two-step reaction that includes chlorination and then the
reaction with N-cyclohexyldithiocarbamate cyclohexyl
300 and 75.5 MHz, respectively (Bruker AC 300), in
CDCl3 and DMSO-d6 solution with tetramethylsilane as
an internal standard. The NMR analysis was performed
at Organic Chemistry Department, Masaryk University,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Synthesis and Antimicrobial Activity of Methyl 2-(2-(2-Arylquinazolin-4-yl)
sulfanyl)acetylamino Alkanoates
Brno, Czech Republic. Elemental analyses were performed
on a FlashEA 1112 instrument at the Microanalytical Labo-
ratory, Faculty of Science, Suez Canal University, Ismailia,
Egypt. Compounds 1a–b and 2a–b were prepared, in our
laboratory, according to reported procedures [17,18,34,35].
solution, water dried, and finally evaporated under
reduced presssure. The residue was recrystallized from
ethanol (charcoal).
2-Phenylquinazoline-4(3H)-thione (4a)[36].
Method A. (ethanol 95%–DMF) yellowish crystals 1.32 g
(92%) 5a, mp: 220–221°C Lit. 221–223°C; 1H NMR
(300 MHz, CDCl3): δ = 13.85 (1H, bs, NH), 8.63 (1H, d,
J = 6.0 Hz, Ar–H), 8.17 (2H, d, J = 6.0 Hz, Ar–H),
7.93–7.77 (2H, m, Ar–H), 7.62–7.57 (4H, m, Ar–H); 13C
NMR spectrum (75 MHz, CDCl3): δ = 188.4 (C═S),
152.0, 144.8, 135.9, 132.7, 131.9, 129.8, 128.9, 128.6,
128.4, 128.2, 128.1 (C–Ar). Found %: C: 70.40; H: 4.11;
N: 11.64. For C14H10N2S (238.06), calculated %: C:
70.56; H: 4.23; N: 11.76.
Preparation
of
thiating
reagent
N-cyclohexyldithiocarbamate cyclohexyl ammonium salt
(3). To a mixture of freshly distilled cyclohexyl amine
(60 mmol) and water (50 mL) was added carbon disulfide
(21 mmol) dropwise. The reaction mixture was stirred
overnight at room temperature. The white solid obtained
was filtered, washed with water, dried, and crystalized
from ethanol to provide pure product of cyclohexylamine
cyclohexyl ammonium dithiocarbamate (3). White
1
crystals (98%) 3, mp: 188–189°C; H NMR (300 MHz,
Method B. 0.08 g or 35%.
Method C. 0.03 g or 14%.
2-(4-Methoxyphenyl)-3H-quinazoline-4-thione (4b)[36].
CDCl3): δ = 8.01 (3H, bs, 3NH), 4.15–3.95 (1H, m, CH),
3.05–2.96 (1H, m, CH), 1.98–0.96 (20H, m, 10CH2); 13C
NMR spectrum (75 MHz, CDCl3): δ = 212.4 (C═S), 55.3
(CH), 50.0 (CH), 32.3 (2CH2), 30.9 (2CH2), 25.8 (CH2),
25.5 (2CH2), 25.1 (CH2), 24.3 (2CH2). Found %: C:
56.63; H: 9.28; N: 10.06. For C13H26N2S2 (274.2),
calculated %: C: 56.88; H: 9.55; N: 10.21.
(Ethanol 95%–DMF) yellowish crystals 0.82 g (89%) 5b,
mp: 195–196°C Lit. 200–201°C; 1H NMR (300 MHz,
CDCl3): δ = 13.71 (1H, bs, NH), 8.60 (1H, d, J = 6.0 Hz,
Ar–H), 8.19 (2H, d, J = 6.0 Hz, Ar–H), 7.88 (1H, t,
J = 6.0 Hz, Ar–H), 7.75 (1H, d, J = 9.0 Hz, Ar–H), 7.56
(1H, t, J = 6.0 Hz, Ar–H), 7.11 (2H, d, J = 9.0 Hz, Ar–
H), 3.87 (3H, s, OCH3); 13C NMR spectrum (75 MHz,
CDCl3): δ = 187.9 (C═S), 162.5, 151.5, 135.9, 130.7,
129.8, 128.5, 128.0, 127.8, 124.6, 114.4 (C–Ar),
55.9(OCH3). Found %: C: 66.92; H: 4.37; N: 10.27. For
C15H12N2OS (268.1), calculated %: C: 67.14; H: 4.51; N:
10.44.
General procedures for preparation of 2-arylquinazolin-4
(3H)-thione (4a–b).
Method A. from chloroquinazoline and the reagent
N-cyclohexyldithiocarbamate cyclohexyl ammonium salt
3.
To a solution of chloroquinazoline 2a–b (2.5 mmol) in
CHCl3 (25 mL) was added N-cyclohexyldithiocarbamate
cyclohexyl ammonium salt 3 (0.69 g, 2.5 mmol). The
reaction mixture was refluxed at 61°C for 12 h. The
reaction mixture was evaporated under reduced pressure,
and 25 mL of ethanol was added to the solid residue. The
yellowish precipitate was filtered to give the desired
product, crystalized from the appropriate solvent.
General procedures for preparation of ethyl (2-
arylquinazolin-4-ylsulfanyl) acetate (5a–b). To a solution
of 2-arylquinazolin-4(3H)-thione 4a–b (1.0 mmol) in
ethyl alcohol (30 mL) was added ethyl chloroacetate
(1.2 mL, 1.0 mmol) and triethyl amine (1.2 mL,
1.2 mmol). The reaction mixture was stirred under reflux
for 12 h. The reaction mixture was filtered and poured
over ice cooled water 50 mL and gave white precipitate
Method B. from 4-chloro-2-phenylquinazoline (2a) and
filtered and dried. The resultant solid was crystalized from
ethanol 95%–water to give the pure ester 5a–b.
thiourea.
A solution of 4-chloro-2-phenylquinazoline (2a) (0.24 g,
1.0 mmol), thiourea (0.15 g, 2.0 mmol), and sodium
methoxide (0.15 g, 3.0 mmol) in 100 mL of absolute
methyl alcohol was refluxed for 6 h. The solution was
concentrated to a small volume and diluted with 250 mL
of water. On acidifying with acetic acid, a yellowish
product formed was separated by filtration, washed with
water, and dried. The yield was 0.08 g or 35%.
Ethyl (2-phenylquinazolin-4-ylsulfanyl) acetate (5a).
White crystals 0.54 g (80%) 5a, mp: 180–181°C; 1H
NMR (300 MHz, CDCl3): δ = 8.64–8.62 (2H, m, Ar–H),
8.12–8.03 (2H, m, Ar–H), 7.86 (1H, t, J = 9.0 Hz, Ar–
H), 7.60–7.53 (4H, m, Ar–H), 4.30–4.22 (4H, m, OCH2,
SCH2), 1.31 (3H, t, J = 6.0 Hz, CH3); 13C NMR
spectrum (75 MHz, CDCl3): δ = 172.7 (C═O), 168.9,
158.9, 149.0, 137.8, 133.9, 130.6, 129.1, 128.6, 128.4,
126.9, 123.7 (C–Ar), 61.9 (OCH2), 32.2 (SCH2), 14.2
(CH3). Found %: C: 66.35; H: 4.82; N: 8.47. For
C18H16N2O2S (324.1), calculated %: C: 66.64; H: 4.97;
Method C. from 2-phenylquinazolin-4(3H)-one 1a and
P2S5.
2-Phenylquinazolin-4(3H)-one 1a (0.22 g, 1.0 mmol)
was boiled with phosphorus pentasulfide (0.44 g,
2.0 mmol) for 2 h in 45 mL of xylene. The mixture was
cooled, diluted with CHCl3, washed with NaHCO3
N: 8.64.
Ethyl [2-(4-methoxyphenyl)quinazolin-4-ylsulfanyl] acetate
(5b). White crystals 0.65 g (58%) 6b, mp: 105–106°C;
1H NMR (300 MHz, CDCl3): δ = 8.55 (2H, d,
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M. I. Megahed and W. Fathalla
Vol 000
J = 8.0 Hz, Ar–H), 8.04–7.95 (2H, m, Ar–H), 7.82–7.78
(1H, t, J = 8.0 Hz, Ar–H), 7.51–7.47 (1H, t, J = 8.0 Hz,
Ar–H), 7.01 (2H, d, J = 8.0 Hz, Ar–H), 4.25–4.18 (4H,
m, OCH2, SCH2), 3.89 (3H, s, OCH3) 1.29–1.25 (3H, t,
J = 8.0 Hz, CH3). Found %: C: 64.27; H: 5.01; N: 7.69.
For C19H18N2O3S (354.10), calculated %: C: 64.39; H:
5.12; N: 7.90.
procedure was repeated several times to ensure the
complete removal of dicyclohexylurea. The filtrate was
washed successively with saturated NaCl solution, 5%
NaHCO3 solution, 1M HCl, and water. After drying over
anhydrous Na2SO4, the solvent was evaporated, and the
remaining residue was crystallized from ethyl acetate-
petroleum ether and afforded S-quinazoline amino acid
esters 7–8(a–f).
General procedures for preparation of (2-arylquinazolin-4-
ylsulfan-yl)acetic acid (6a–b). To a solution ester 5a–b
Methyl
(2-(2-(2-phenylquinazolin-4-yl)sulfanyl)acetyl)
aminoacetate (7a). White crystals 1.54 g (94%) 7a, mp:
(1.0 mmol) in methyl alcohol (30 mL) was added
potassium hydroxide (0.11 g, 2.0 mmol) solution in
10 mL H2O. The reaction mixture was stirred at room
temperature for 4 h till complete consumption of the ester
(monitored by thin-layer chromatography). The reaction
mixture was evaporated under reduced pressure, diluted
with water, and acidified by conc. HCl. The separated
precipitate was filtered off and washed several times with
water and dried. Crystallization from ethanol gave pure
crystals from carboxylic acid 6a–b.
(2-Phenylquinazolin-4-ylsulfanyl)acetic acid (6a). White
crystals 0.84 g (75%) 6a, mp: 160–161°C; 1H NMR
(300 MHz, CDCl3): δ = 10.60 (1H, bs, OH), 8.58–8.55
(2H, m, Ar–H), 8.14 (1H, d, J = 9.0 Hz, Ar–H), 8.01
(2H, s, Ar–H), 7.73–7.68 (1H, m, Ar–H), 7.57–7.55 (3H,
s, Ar–H), 4.29 (2H, s, SCH2); 13C NMR spectrum
(75 MHz, CDCl3): δ = 170.7 (C═O), 170.2 (Cq), 158.3
(Cq), 148.2 (Cq), 137.4 (Cq), 135.3 (CHAr), 131.5
(CHAr), 129.1 (CHAr), 128.8 (CHAr), 128.4 (CHAr),
124.1 (CHAr), 121.9 (Cq), 32.6 (SCH2). Found %: C:
64.73; H: 3.86; N: 9.26. For C16H12N2O2S (296.1),
calculated %: C: 64.85; H: 4.08; N: 9.45.
1
162–163°C; H NMR (300 MHz, CDCl3): δ = 8.63–8.60
(2H, m, Ar–H), 8.12–8.06 (2H, m, Ar–H), 7.90 (1H, t,
J = 9.0 Hz, Ar–H), 7.63–7.54 (4H, m, Ar–H), 7.41 (1H,
bs, NH), 4.23 (2H, s, SCH2), 4.02 (2H, d, J = 6.0 Hz,
NHCH2), 3.57 (3H, s, OCH3); 13C NMR spectrum
(75 MHz, CDCl3): δ = 171.9 (C═O), 169.6 (C═O), 168.6
(Cq), 158.9 (Cq), 149.2 (Cq), 137.4 (Cq), 134.3 (CHAr),
130.9 (CHAr), 129.2 (CHAr), 128.7 (CHAr), 128.5
(CHAr), 127.2 (CHAr), 123.7 (CHAr), 122.2 (Cq), 52.2
(OCH3), 41.6 (NHCH2), 32.6 (SCH2). Found %: C:
61.84; H: 4.28; N: 11.36. For C19H17N3O3S (367.1),
calculated %: C: 62.11; H: 4.66; N: 11.44.
Methyl
(3-(2-(2-phenylquinazolin-4-yl)sulfanyl)acetyl)
aminopropanoate (7b). White crystals 0.50 g (97%) 7b,
1
mp: 140–141°C; H NMR (300 MHz, CDCl3): δ = 8.60–
8.58 (2H, m, 2Ar–H), 8.09–8.02 (2H, m, Ar–H), 7.90
(1H, t, J = 4.0 Hz, Ar–H), 7.60–7.52 (4H, m, Ar–H),
7.38 (1H, bs, NH), 4.11 (2H, s, SCH2), 3.42 (2H, q,
J = 6.0 Hz, NHCH2), 3.22 (3H, s, OCH3), 2.34 (2H, t,
J = 6.0 Hz, CH2). Found %: C: 62.84; H: 4.81; N: 10.87
For C20H19N3O3S (381.1), calculated %: C: 62.97; H:
5.02; N: 11.02.
[2-(4-Methoxyphenyl)quinazolin-4-ylsulfanyl]acetic
acid
Methyl
(4-(2-(2-phenylquinazolin-4-yl)sulfanyl)acetyl)
(6b). White crystals 1.21 g (88%) 6b, mp: 120–121°C;
1H NMR (300 MHz, CDCl3): δ = 12.96 (1H, bs, OH),
8.51 (2H, d, J = 8.0 Hz, Ar–H), 8.09 (1H, d, J = 8.0 Hz,
Ar–H), 7.95 (2H, d, J = 8.0 Hz, Ar–H), 7.65 (1H, s, Ar–
H), 7.07 (2H, d, J = 8.0 Hz, Ar–H), 4.25 (2H, s, SCH2),
3.85 (3H, S, OCH3). Found %: C: 62.35 H: 4.13; N:
8.37. For C17H14N2O3S (326.1), calculated%: C: 62.56
H: 4.32; N: 8.58.
aminobutanoate (7c).
White crystals 0.35 g (65%) 7c,
1
mp: 145–146°C; H NMR (300 MHz, CDCl3): δ = 8.58–
8.56 (2H, m, 2Ar–H), 8.10–8.03 (2H, m, Ar–H), 7.89
(1H, t, J = 8.0 Hz, Ar–H), 7.60–7.49 (4H, m, Ar–H) 7.13
(1H, bs, NH), 4.13 (2H, s, SCH2), 3.48 (3H, s, OCH3),
3.22 (2H, q, J = 6.0 Hz, NHCH2), 2.11 (2H, t,
J = 6.0 Hz, CH2), 1.94–1.63(2H, m, CH2). Found %: C:
63.63; H: 5.22; N: 10.48. For C21H21N3O3S (395.1),
calculated %: C: 63.78; H: 5.35; N: 10.63.
General procedures for preparation of methyl 2-(2-(2-
arylquinazolin-4-yl)sulfanyl)acetylamino alkanoates 7–8(a–f)
by DCC coupling method. To a cold solution (ꢀ5°C) of
Methyl
(2-(2-(2-phenylquinazolin-4-yl)sulfanyl)acetyl)
aminopropanoate (7d). White crystals 0.74 g (60%) 7d,
1
amino acid ester hydrochloride (4.4 mmol) in acetonitrile
(40 mL) containing triethyl amine (0.62 mL, 4.4 mmol),
1-hydroxybenzotriazole (HOBt) (0.59 g, 4.4 mmol),
dicyclohexylcarbodiimide (DCC) (0.88 g, 4.4 mmol), and
the carboxylic compounds (6a–b) (1.5 g, 4.4 mmol) were
added successively. The solution was stirred at 0°C for
2 h and at room temperature for 8 h. The precipitated
dicyclohexylurea was filtered off, and the filtrate was
evaporated under reduced pressure. The residue was
extracted with ethyl acetate, filtered off evaporated, and
extracted once again with ethyl acetate. This workup
mp: 165–166°C; H NMR (300 MHz, CDCl3): δ = 8.59–
8.54 (2H, m, Ar–H), 8.08–8.02 (2H, m, Ar–H), 7.89 (1H,
t, J = 8.0 Hz, Ar–H), 7.58–7.51 (5H, m, Ar–H, NH),
4.54–4.50 (1H, m, NHCH), 4.16 (2H, dd, J = 28.0,
16.0 Hz, SCH2), 3.49 (3H, s, OCH3), 1.16 (3H, d,
J = 6.0 Hz, CH3). Found %: C: 62.75; H: 4.83; N: 10.72.
For C20H19N3O3S (381.1), calculated %: C: 62.97; H:
5.02; N: 11.02.
Methyl
(2-(2-(2-phenylquinazolin-4-yl)sulfanyl)acetyl)
amino-3-methylbutanoate (7e).
(52%) 7e, mp: 142–143°C; H NMR (300 MHz, CDCl3):
White crystals 0.39 g
1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Synthesis and Antimicrobial Activity of Methyl 2-(2-(2-Arylquinazolin-4-yl)
sulfanyl)acetylamino Alkanoates
δ = 8.65–8.50 (2H, m, Ar–H), 8.20–8.17 (2H, m, Ar–H),
7.90 (1H, t, J = 8.0 Hz, Ar–H), 7.78–7.50 (5H, m, Ar–H,
NH), 4.27 (2H, dd, J = 32.0, 15.0 Hz, SCH2), 3.56 (3H,
s, OCH3), 2.24–2.14 (1H, m, CH), 0.75–0.67 (6H, m,
CH3); 13C NMR spectrum (75 MHz, CDCl3): δ = 172.2
(C═O), 170.5 (C═O), 167.4 (Cq), 158.6 (Cq), 148.6 (Cq),
137.5 (Cq), 135.0 (CHAr), 131.3 (CHAr), 129.0 (CHAr),
128.8 (CHAr), 128.5 (CHAr), 128.2 (CHAr), 124.0
(CHAr), 122.0 (Cq), 58.4 (NHCH), 52.1 (OCH3), 33.5
(SCH2), 30.6 (CH), 19.3 (CH3), 18.3 (CH3). Found %: C:
64.32; H: 5.48; N: 10.14. For C22H23N3O3S (409.15),
calculated %: C: 64.53; H: 5.66; N: 10.26.
m, Ar–H), 7.17 (1H, bs, NH), 7.04 (2H, d, J = 8.0 Hz,
Ar–H), 4.10 (2H, s, SCH2), 3.89 (3H, s, OCH3), 3.48
(3H, s, OCH3), 3.22 (2H, q, J = 8.0 Hz, NHCH2), 2.11
(2H, t, J = 8.0 Hz, CH2CO), 1.67–1.62 (2H, m, CH2).
Found %: C: 61.96; H: 5.34; N: 9.67. For C22H23N3O4S
(425.14), calculated %: C: 62.10; H: 5.45; N: 9.88.
Methyl (2-(2-(2-(4-methoxyphenyl)quinazolin-4-yl)sulfanyl)
acetyl) aminopropanoate (8d).
White crystals 0.97 g
1
(78%) 8d, mp: 130–131°C; H NMR (300 MHz, CDCl3):
δ = 8.56–8.50 (2H, d, J = 8.0 Hz, Ar–H), 8.06–7.98 (2H,
m, Ar–H), 7.85 (1H, t, J = 8.0 Hz, Ar–H), 7.55–7.49
(2H, m, Ar–H, NH), 7.03 (2H, d, J = 8.0 Hz, Ar–H),
4.55–4.51 (1H, m, NHCH), 4.16 (2H, dd, J = 32.0,
15.0 Hz, SCH2), 3.89 (3H, s, OCH3), 3.51 (3H, s,
OCH3), 1.18 (3H, d, J = 6.0 Hz, CH3). Found %: C:
61.14; H: 5.02; N: 10.05. For C21H21N3O4S (411.13),
Methyl
(2-(2-(2-phenylquinazolin-4-yl)sulfanyl)acetyl)
amino-4-methylpentanoate (7f).
White crystals 1.13 g
1
(79%) 7f, mp: 140–141°C; H NMR (300 MHz, CDCl3):
δ = 8.61–8.58 (2H, m, Ar–H), 8.12–8.05 (2H, m, Ar–H),
7.90 (1H, t, J = 8.0 Hz, Ar–H), 7.62–7.56 (4H, m, Ar–H),
7.35 (1H, d, J = 6.0 Hz, NH), 4.60–4.52 (1H, m, NHCH),
4.18 (2H, dd, J = 32.0, 15.0 Hz, SCH2), 3.51 (3H, s,
OCH3), 1.44–1.12 (3H, m, CH2, CH), 0.70–0.58 (6H, m,
CH3); 13C NMR spectrum (75 MHz, CDCl3): δ = 172.2
(C═O), 170.5 (C═O), 168.2 (Cq), 158.9 (Cq), 149.1 (Cq),
137.4 (Cq), 134.3 (CHAr), 130.9 (CHAr), 129.2 (CHAr),
128.7 (CHAr), 128.5 (CHAr), 127.3 (CHAr), 123.8
(CHAr), 122.1 (Cq), 52.0 (OCH3), 51.0 (NHCH), 32.7
(SCH2), 24.6 (CH2), 22.5 (CH), 21.5 (2CH3). Found %:
C: 65.01; H: 5.72; N: 9.76. For C23H25N3O3S (423.16),
calculated %: C: 61.30; H: 5.14; N: 10.21.
Methyl (2-(2-(2-(4-methoxyphenyl)quinazolin-4-yl)sulfanyl)
acetyl) amino-3-methylbutanoate (8e).
White crystals
1
1.11 g (59%) 8e, mp: 110–111°C; H NMR (300 MHz,
CDCl3): δ = 8.52 (2H, d, J = 8.0 Hz, Ar–H), 8.04–7.96
(2H, m, Ar–H), 7.82 (1H, t, J = 8.0 Hz, Ar–H), 7.51 (1H,
t, J = 8.0 Hz, Ar–H), 7.32 (1H, bs, NH), 7.01 (2H, d,
J = 8.0 Hz, Ar–H), 4.48–4.44 (1H, m, NHCH), 4.14 (2H,
dd, J = 32.0, 15.0 Hz, SCH2), 3.87 (3H, s, OCH3), 3.46
(3H, s, OCH3), 1.97–1.90 (1H, m, CH), 1.08–1.05 (6H,
m, CH3). Found %: C: 62.62; H: 5.52; N: 9.39. For
C23H25N3O4S (439.16), calculated %: C: 62.85; H: 5.73;
calculated %: C: 65.23; H: 5.95; N: 9.92.
Methyl (2-(2-(2-(4-methoxyphenyl)quinazolin-4-yl)sulfanyl)
acetyl) amino acetate (8a). White crystals 1.40 g (96%)
N: 9.56.
Methyl (2-(2-(2-(4-methoxyphenyl)quinazolin-4-yl)sulfanyl)
8a, mp: 150–151°C; 1H NMR (300 MHz, CDCl3):
δ = 8.54 (2H, d, J = 8.0 Hz, Ar–H), 8.05–7.98 (2H, m,
Ar–H), 7.86–7.83 (1H, t, J = 8.0 Hz, Ar–H), 7.55–7.51
(1H, m, Ar–H), 7.41 (1H, bs, NH), 7.04 (2H, d,
J = 8.0 Hz, Ar–H), 4.17 (2H, s, SCH2), 3.98 (2H, d,
J = 6.0 Hz, NHCH2), 3.89 (3H, s, OCH3), 3.55 (3H, s,
OCH3). Found %: C: 60.28; H: 4.62; N: 10.42. For
C20H19N3O4S (397.11), calculated %: C: 60.44; H: 4.82;
acetyl) amino-4-methylpentanoate (8f).
White crystals
1
0.69 g (64%) 8f, mp: 120–121°C; H NMR (300 MHz,
CDCl3): δ = 8.53 (2H, d, J = 8.0 Hz, Ar–H), 8.06–7.98
(2H, m, Ar–H), 7.85 (1H, t, J = 8.0 Hz, Ar–H), 7.53 (1H,
t, J = 8.0 Hz, Ar–H), 7.33 (1H, bs, NH), 7.03 (2H, d,
J = 8.0 Hz, Ar–H), 4.56–4.51 (1H, m, NHCH), 4.14 (2H,
dd, J = 32.0, 15.0 Hz, SCH2), 3.89 (3H, s, OCH3), 3.49
(3H, s, OCH3), 1.38–1.20 (3H, m, CH2, CH), 0.82–0.81
(6H, m, CH3). Found %: C: 63.40; H: 6.87; N: 9.13. For
C24H27N3O4S (453.17), calculated %: C: 63.56; H: 6.00;
N: 9.26.
N: 10.57.
Methyl (3-(2-(2-(4-methoxyphenyl)quinazolin-4-yl)sulfanyl)
acetyl) aminopropanoate (8b).
White crystals 0.85 g
1
(92%) 8b, mp: 155–156°C; H NMR (300 MHz, CDCl3):
δ = 8.54 (2H, d, J = 8.0 Hz, Ar–H), 8.05–7.97 (2H, m,
Ar–H), 7.86–7.82 (1H, t, J = 8.0 Hz, Ar–H), 7.55–7.51
(1H, t, J = 8.0 Hz, Ar–H), 7.32 (1H, bs, NH), 7.04 (2H,
d, J = 8.0 Hz, Ar–H), 4.08 (2H, s, SCH2), 3.90 (3H, s,
OCH3), 3.43 (2H, q, J = 6.0 Hz, NHCH2), 3.22 (3H, s,
OCH3), 2.32 (2H, t, J = 6.0 Hz, CH2). Found %: C:
61.08; H: 5.02; N: 10.01. For C21H21N3O4S (411.13),
Biological activity materials and methods.
Bacterial strain: Gram-positive bacteria S. aureus and
Gram-negative bacteria E. coli were used to evaluate the
antibacterial activity of the synthesized compounds.
Fungal strain: Clinical culture (C. albicans) was used to
evaluate the antifungal activity of the synthesized
compounds.
Reference therapeutic drugs: Three antibiotic drugs were
used in this work:
calculated %: C: 61.30; H: 5.14; N: 10.21.
Methyl (4-(2-(2-(4-methoxyphenyl)quinazolin-4-yl)sulfanyl)
acetyl) aminobutanoate (8c). White crystals 0.54 g (62%)
8c, mp: 160–161°C; 1H NMR (300 MHz, CDCl3):
δ = 8.52 (2H, d, J = 8.0 Hz, Ar–H), 8.05–7.98 (2H, m,
Ar–H), 7.85 (1H, t, J = 8.0 Hz, Ar–H), 7.55–7.51 (1H,
1) tetracycline (30 μg),
2) erythromycin (15 μg), and
3) novobiocin (30 μg).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. I. Megahed and W. Fathalla
Vol 000
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet