Synthesis and Antimicrobial Activity of Methyl 2-(2-(2-Arylquinazolin-4-yl)oxy) Acetylamino Alkanoates

Article abstract of DOI:10.1002/jhet.3347

A series of methyl 2-(2-(2-arylquinazolin-4-yl)oxy) acetylamino alkanoate have been developed via N,N′-dicyclohexylcarbodiimide coupling of (2-arylquinazolin-4-yloxy) acetic acids with amino acid ester hydrochlorides. The O-substituted carboxylic acids we

Full text of DOI:10.1002/jhet.3347

Month 2018
Synthesis and Antimicrobial Activity of Methyl 2-(2-(2-Arylquinazolin-
4-yl)oxy) Acetylamino Alkanoates
a
a
M. Megahed, W. Fathalla,
and Amer A. Alsheikhb
*
aPhysics and Math. Engineering Dept., Faculty of Engineering, Port-Said University, Port Said, Egypt
bInstitute of Physical and Applied Chemistry (IPAC), Faculty of Chemistry, Brno University of Technology, Brno,
Czech Republic
*E-mail: walid3369@yahoo.com
Received June 25, 2018
DOI 10.1002/jhet.3347
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
A series of methyl 2-(2-(2-arylquinazolin-4-yl)oxy) acetylamino alkanoate have been developed via N,N0-
dicyclohexylcarbodiimide coupling of (2-arylquinazolin-4-yloxy) acetic acids with amino acid ester hydro-
chlorides. The O-substituted carboxylic acids were prepared by two-step reactions from the corresponding 2-
arylquinazolin-4(3H)-one starting with chemoselective O-alkylation with ethyl chloroacetate and then hy-
drolysis of the produced esters. The reason for this O-chemoselective behavior of 2-arylquinazolin-4(3H)-
one toward electrophiles was explained by theoretical density functional theory computational calculations
on the model compound 2-phenylquinazolin-4(3H)-one. The antimicrobial activity of the synthesized com-
pounds was evaluated, showing the best inhibition zone for (2-arylquinazolin-4-yloxy) acetic acids, methyl
2-(2-(2-arylquinazolin-4-yl)oxy) acetylamino acetates, and methyl 2-(2-(2-phenylquinazolin-4-yl)oxy)
acetylamino-3-methylbutanoate.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
RESULTS AND DISCUSSION
Quinazoline [1] is one of the most frequently
encountered heterocycles in medicinal chemistry.
Quinazoline derivatives have shown significant biological
activities such as analgesic [2], anti-inflammatory [3],
antifungal [4,5], antibacterial [6,7], anticancer [8],
antitumor [9,10], anti-HIV [11], antituberculosis [12], and
anticonvulsant [13] activities. Non-proteinogenic amino
acids are a major component in a number of drugs
including β-lactam antibiotics, glutamate antagonists,
and antiviral drugs [14–16]. The attachment of a new
quinazoline ring to proteinogenic or non-proteinogenic
amino acid esters might provide structures with
interesting conformation, stability, and biological activity.
Consequently, we found it interesting to prepare a number
of quinazoline derivatives linked to amino acid esters via
acetyl spacer and evaluate their antimicrobial activities on
the basis of chemoselective reactions of heterocyclic
amides.
2-Arylquinazolin-4(3H)-ones 4a–b are excellent
precursors for the structure modification of quinazoline
ring system on the basis of chemoselective reactions of
heterocyclic amides. These 2-arylquinazolin-4(3H)-ones
4a–b were prepared by multistep reactions starting
from anthranilic acid [17–19] as described in Scheme 1.
The ambident nucleophile 4a–b reacted with ethyl
chloroacetate in the presence of K2CO3, which afforded
only the chemoselective O-alkylation products ethyl 2-(2-
arylquinazolin-4-yloxy) acetates 5a–b in good yields
(Scheme 1).
Amides and heterocyclic amide reaction with
electrophiles is an important task in organic synthesis.
Earlier results show that these compounds may react
with electrophiles at nitrogen (N), at oxygen (O), or at
both heteroatoms [6,20–24]. This behavior is due to
negative charge delocalization about both atoms in amides
(Fig. 1). Several factors should be taken into consideration
© 2018 Wiley Periodicals, Inc.

M. Megahed, W. Fathalla, and A. A. Alsheikh
Vol 000
Scheme 1. Preparation (2-arylquinazolin-4-yloxy) acetic acid (6a–b).
Figure 1. Ambident nucleophile behavior of 2-phenyl-quinazolin-4(3H)-
ones 4a.
to analyze this behavior such as substituents, substrates,
solvents, and electrophiles.
Figure 2. Optimized structures with atom numbering for 2-
phenylquinazolin-4(3H)-one 4a.
This ambiguous behavior of heterocyclic amide reaction
with electrophiles could be explained in terms of hard and
soft acids and bases (HSAB) principle by evaluation of
hardness and softness of the nitrogen and oxygen atoms in
heterocyclic amides. It is very important to apply density
functional theory (DFT) calculations for softness and
hardness evaluation through the calculation of a number
of parameters such as molecular orbital coefficients,
electron density, and Fukui functions on the model
2-phenyl-quinazolin-4(3H)-one 4a. These calculations
should be evaluated parallel to our experimental results
and results obtained by the reaction of heterocyclic amides
with electrophiles presented by other research groups,
which might give us a clear picture of this behavior. The
calculations were performed using MOLPRO (Stuttgart,
Germany) program package on the model compound 4a.
The optimized geometric structure of 4a compound
calculated using DFT(B3LYP)/STO-3G level of theory is
presented in Figure 2.
hard or soft reagents. The nucleophilic and electrophilic
Fukui functions for all atoms of the 4a molecule are
presented in Table 1. For simplicity, we will focus only
on the values of Fukui function related only to the
competing ambident nucleophilic sites. Table 1 shows
with no doubts that the O-atom is the harder part of the
ambident nucleophile with smaller f ꢀk values.
Electron density and charge distribution on atoms of 4a
are presented in Figure 3c and Table 2. Both parameters
suggests that the O-atom is the hard site of the ambident
nucleophile 2-phenylquinazolin-4(3H)-one 4a.
Table 1
The Fukui indices of the atoms in molecule 4a calculated at
DFT(B3LYP)/6311G level of theory using Mulliken population analysis.
qk
(N + 1)
qk
(N ꢀ 1)
Atom
qk(N)
f kþ
f kꢀ
O1
N2
N3
C4
C5
C6
C7
C8
ꢀ0.212
ꢀ0.247
ꢀ0.287
ꢀ0.077
ꢀ0.073
ꢀ0.075
ꢀ0.078
ꢀ0.065
ꢀ0.275
ꢀ0.298
ꢀ0.305
ꢀ0.104
ꢀ0.127
ꢀ0.101
ꢀ0.113
ꢀ0.097
ꢀ0.117
ꢀ0.158
ꢀ0.246
ꢀ0.059
ꢀ0.032
ꢀ0.055
ꢀ0.055
ꢀ0.038
ꢀ0.063
ꢀ0.051
ꢀ0.018
ꢀ0.027
ꢀ0.054
ꢀ0.026
ꢀ0.035
ꢀ0.032
ꢀ0.095
ꢀ0.089
ꢀ0.041
ꢀ0.018
ꢀ0.041
ꢀ0.02
The Fukui function is an important parameter used to
distinguish between soft and hard sites of different
nucleophiles [25]. The regions of a molecule where the
Fukui function is large are chemically softer than the
regions where the Fukui function is small, and by
invoking the HSAB principle in a local sense, one may
establish the behavior of the different sites with respect to
ꢀ0.023
ꢀ0.027
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Synthesis and Antimicrobial Activity of Some O-Substituted Amino Acid
Coupled Quinazoline Derivatives
(a)
(b)
(c)
Figure 3. Calculated 3D plots of molecular orbitals [HOMO (a) and LUMO (b)] and electron densities (c) for the molecule 4a by (B3LYP)/STO-3G
method. [Color figure can be viewed at wileyonlinelibrary.com]
From the computational analysis in Figure 3a and 3b and
Tables 1 and 2, we conclude that the oxygen atom of the
ambident nucleophile 4a combines both the hard and soft
Table 2
Mulliken charge distribution for 2-phenylquinazolin-4(3H)-one 4a.
Mulliken
atomic
charges
Mulliken
atomic
charges
Mulliken
atomic
charges
characters. We predict that the reaction of the title
compound 4a with either hard or soft electrophiles will
take place at the oxygen atom in terms of HSAB
principle. Taking a close look at the structure feature of
our model compound lactim form (Fig. 1 4a, II), the
oxygen atom is a part of a continuous conjugated system.
Also, the phenyl group at position 2 is crucial and is
taking part in the conjugated system. This characteristic
structure increases the energy of the HOMO at the
O-atom and consequently softens the oxygen atom and is
susceptible to interact with soft electrophiles. Earlier
results show that the reaction of 2-phenylquinazolin-
4(3H)-one 4a with alkyl halides in the presence of K2CO3
in dimethylformamide (DMF) gave chemoselective
O-substituted quinazoline derivatives [24]. On the other
hand, the reaction of 2-benzylquinazolin-4(3H)-one with
alkyl halides in the presence of K2CO3 in DMF gave a
mixture of N-substituted and O-substituted quinazoline
derivatives (N-substitution was the major product)
[20,21,24].
Atom
Atom
Atom
O1
N2
N3
C4
C5
C6
C7
ꢀ0.212
ꢀ0.247
ꢀ0.287
ꢀ0.077
ꢀ0.073
ꢀ0.075
ꢀ0.078
C8
C9
ꢀ0.065
ꢀ0.007
0.174
C15
C16
C17
H18
H19
H20
H21
ꢀ0.031
ꢀ0.079
ꢀ0.071
0.083
0.084
0.092
C10
C11
C12
C13
C14
0.211
ꢀ0.073
0.063
ꢀ0.074
0.092
The 3D plots of molecular orbitals [highest occupied
molecular orbital (HOMO) and lowest unoccupied
molecular orbital (LUMO)] for 2-phenylquinazolin-
4(3H)-one 4a calculated using DFT(B3LYP)/STO-3G
method are presented in Figure 3a and 3b. HOMO
described as electron donor tends to give electrons, and
hence, the soft potential is directly related to the energy
of the HOMOs. In the title compound 4a (Fig. 3a);
oxygen atom has HOMO of slightly higher energy than
has nitrogen atom.
Journal of Heterocyclic Chemistry
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M. Megahed, W. Fathalla, and A. A. Alsheikh
Vol 000
(2-Arylquinazolin-4-yloxy) acetic acids 6a–b in pure
state and in good yields were successfully achieved by
saponification of esters 5a–b with aqueous KOH in
methanol for 4 h (Scheme 1). Carboxylic acids 6a–b
are excellent precursors for structure modification of
quinazoline moiety by attaching amino acid residue
via well-known N,N0-dicyclohexylcarbodiimide (DCC)
coupling method [26,27]. Treatment of carboxylic acid
6a–b with amino acid ester hydrochlorides in the
presence of triethylamine and coupling reagents DCC
and 1-hydroxybenzotriazole (HOBt) afforded methyl
2-(2-(2-arylquinazolin-4-yl)oxy) acetylamino alkanoates
7–8(a–f) in good yield (Scheme 2).
fungus strain (Candida albicans). The method applied
is paper-disc agar plate method [28], using two
concentrations of 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
mm as shown in Tables 3 and 4.
From the results listed in Tables 3 and 4, we can
conclude the following:
1. Table 3 shows general screening for all synthesized
compounds and reference antibiotics; tetracycline and
novobiocin with concentrations of (30 μg) toward the
microorganisms; Gram-positive bacteria S. aureus,
Gram-negative bacteria E. coli, and pathogenic yeast
C. albicans.
2. Compounds tested: Quinazolinone 4b, ester 5a, acids
6a–b, amino acid derivatives 7e (R1═H, Val), 8a
(R1═OCH3, Gly), 8d (R1═OCH3, Ala), 8e (R1═OCH3,
Val), and 8f (R1═OCH3, Leu) showed moderate to high
activity against Gram-negative bacteria E. coli (IZ
ranging from 0.6 to 1.7 mm) surpassing in some cases
the activity of the standard reference antibiotics applied:
tetracycline (IZ = 0.7 mm) and novobiocin (no IZ)
(Table 3).
3. Compounds tested: Acids 6a–b, amino acid derivatives
7a (R1═H, Gly), 7c (R1═H, γ-Aba), and 7e (R1═H,
Val) showed high activity against Gram-positive bac-
teria S. aureus (IZ ranging from 0.8 to 2.0 mm) sur-
passing the activity of the standard reference antibiotics
applied: tetracycline (IZ = 0.6 mm) and novobiocin
(no IZ), Table 3.
4. Compounds tested: Quinazolinone 4b, ester 5b, acids
6a–b, amino acid derivatives 7a (R1═H, Gly), 7c
(R1═H, γ-Aba), 7e (R1═H, Val), 8a (R1═OCH3, Gly),
8e (R1═OCH3, Val), and 8f (R1═OCH3, Leu) showed
moderate to high activity against pathogenic yeast
The structure assignment of methyl 2-(2-(2-
arylquinazolin-4-yl)oxy) acetylamino alkanoates 7–8(a–f)
1
is based on H and 13C NMR spectroscopy, as well as
physicochemical analysis. The 1H NMR spectrum of
compound 7a in dimethyl sulfoxide (DMSO) showed
triplet signals at 8.73 ppm corresponding to NH proton of
the peptide bond, multiplet signals ranging between 8.53
and 7.53 ppm corresponding to nine aromatic protons,
singlet signal at 5.22 ppm for the OCH2 group, doublet
signal at 3.96 ppm for NCH2 group, and singlet signal at
3.60 ppm for three protons of OCH3. The 13C NMR
spectrum of 7a showed signals for CO group that
appeared at 170.5 and 168.0 ppm; signals for C–Ar
appeared at 166.0, 159.2, 151.9, 137.6, 134.9, 131.3,
129.0, 128.6, 128.0, 127.6, 124.2, and 114.9 ppm; signal
that appeared at 65.2 ppm for OCH2 group; signal that
appeared at 52.2 ppm for OCH3 group; and signal that
appeared at 40.9 ppm for NHCH2 group.
Antibacterial and antifungal activities. The compounds:
Quinazolinone 4a–b, esters 5a–b, acids 6a–b, and methyl
2-(2-(2-arylquinazolin-4-yl)oxy) 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 one
Scheme 2. Synthesis of methyl 2-(2-(2-arylquinazolin-4-yl)oxy) acetylamino alkanoates 7–8(a–f).
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Synthesis and Antimicrobial Activity of Some O-Substituted Amino Acid
Coupled Quinazoline Derivatives
Table 3
Samples (30 μg each) were analyzed using “disc diffusion method”.
Antibacterial activity
Antifungal activity
Zone of inhibition (mm)
Zone of inhibition (mm)
Code no.
Escherichia coli
Staphylococcusaureus
Candida albicans
Control
4a
4b
5a
5b
6a
6b
7a
7b
7c
7d
7e
7f
8a
8b
8c
-ve
-ve
0.7
0.9
-ve
1.7
1.6
-ve
-ve
-ve
-ve
1.6
-ve
0.6
-ve
-ve
0.6
0.8
0.7
0.7
-ve
-ve
-ve
-ve
-ve
-ve
2.0
1.7
0.9
-ve
0.8
-ve
1.8
-ve
-ve
-ve
-ve
-ve
-ve
-ve
0.6
-ve
-ve
-ve
0.8
-ve
0.8
1.8
1.6
0.7
-ve
0.6
-ve
2.0
-ve
0.9
-ve
-ve
-ve
0.6
0.7
1.2
2
8d
8e
8f
Tetracycline
Novobiocin
-ve: abbreviated to no inhibition zone was observed.
Table 4
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
Staphylococcusaureus
Candida albicans
Control
6a
6b
7e
-ve
1.7
1.4
1.9
-ve
-ve
1.4
1.5
1.9
-ve
-ve
1.1
1.0
1.4
2
Erythromycin
-ve: abbreviated to no inhibition zone was observed.
C. albicans (IZ ranging from 0.6 to 2.0 mm). The IZ of
the standard reference antibiotics applied: tetracycline
(IZ = 1.2 mm) and novobiocin (IZ = 2.0 mm) (Table 3).
5. Maximum antimicrobial activity of all screened com-
pounds toward all three microorganisms: Gram-negative
bacteria E. coli and pathogenic yeast C. albicans were
observed for the carboxylic acid derivatives 6a–b and
amino acid derivative 7e (R1═H, Val) (Table 3).
derivative 7e (R1═H, Val) 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 (Table 4).
7. The carboxylic acid derivatives 6a–b and amino acid
derivative 7e (R1═H, Val) showed very high activity
against Gram-positive bacteria S. aureus, with Gram-
negative bacteria E. coli surpassing the activity of the
standard reference antibiotics applied erythromycin,
6. Table 4 shows antimicrobial testing for compounds
carboxylic acid derivatives 6a–b and amino acid
Journal of Heterocyclic Chemistry
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M. Megahed, W. Fathalla, and A. A. Alsheikh
Vol 000
and poured over 50 mL ice-cooled water and gave white
precipitate, filtered, and dried. The resultant solid was
crystallized from 95% ethanol to give the pure ester 5a–b.
while giving good activity against pathogenic yeast
C. albicans (Table 4).
Ethyl (2-phenylquinazolin-4-yloxy) acetate.
White
crystals 0.84 g (75%) 5a, M.p.: 110–111°C; 1H NMR
(300 MHz, CDCl3): δ = 8.75–8.54 (2H, m, Ar–H), 8.26
(1H, d, J = 6.0 Hz, Ar–H), 8.04 (1H, d, J = 9.0 Hz,
Ar–H), 7.85 (1H, t, J = 8.0 Hz, Ar–H), 7.58–7.50 (4H,
m, Ar–H), 5.20 (2H, s, OCH2), 4.28 (2H, q, J = 6.0 Hz,
CH2CH3), 1.31–1.27 (3H, t, J = 6.0 Hz, CH3); 13C NMR
spectrum (75 MHz, CDCl3): δ = 168.3 (C═O), 165.7,
159.4, 152.2, 137.7, 133.9, 130.6, 128.4, 128.4, 128.0,
126.7, 123.5, 114.8 (C–Ar), 63.3 (OCH2), 61.4
(OCH2CH3), 14.2 (CH3). Found %: C, 69.48; H, 5.64; N,
8.88. For C18H18N2O3 (310.13). Calculated %: C, 69.66;
H, 5.85; N, 9.03.
CONCLUSION
A series of methyl 2-(2-(2-arylquinazolin-4-yl)oxy)
acetylamino alkanoates 7–8(a–f) have been developed
on the basis of the O-chemoselective reaction of
2-arylquinazolin-4(3H)-one 4a–b with ethyl chloroacetate
and DCC coupling method with amino acid ester
hydrochloride. The precursor 2-phenylquinazolin-4(3H)-
one 4a chemoselective reactions were studied using
DFT(B3LYP)/6-311G level of theory. According to
computational data, oxygen atom combines between both
soft and harder characters with the model compound
2-phenylquinazolin-4(3H)-one 4a. The antimicrobial
activity of the synthesized compounds was evaluated,
showing the best IZ for glycine 7a and 8a, valine
derivatives 7e and 8e, and the starting carboxylic acid 6a
and 6b. These compounds show high activities toward
Gram-positive bacteria S. aureus, Gram-negative bacteria
E. coli, and pathogenic yeast C. albicans and also have
higher IZ than have the standard reference antibiotics
applied: tetracycline, erythromycin, and novobiocin.
Ethyl [2-(4-methoxy-phenyl)quinazolin-4-yloxy] acetate
(5b).
White crystals 0.74
g
(69%) 5b, M.p.:
1
120–121°C; H NMR (300 MHz, CDCl3): δ = 8.49 (2H,
d, J = 9.0 Hz, Ar–H), 8.22 (1H, d, J = 9.0 Hz, Ar–H),
7.98 (1H, d, J = 6.0 Hz, Ar–H), 7.80 (1H, t, J = 9.0 Hz,
Ar–H), 7.54–7.49 (1H, t, J = 9.0 Hz, Ar–H), 7.02 (2H, d,
J = 9.0 Hz, Ar–H), 5.18 (2H, s, OCH2), 4.29 (2H, q,
J = 6.0 Hz, CH2CH3), 3.89 (3H, s, OCH3), 1.30–1.25
(3H, t, J = 6.0 Hz, CH3); 13C NMR spectrum (75 MHz,
CDCl3): δ = 168.4 (C═O), 165.5, 161.9, 159.2, 152.3,
133.8, 130.4, 130.1, 127.7, 126.2, 123.5, 114.5, 113.8
(C–Ar), 63.3 (OCH2), 61.3 (OCH2CH3), 55.4 (OCH3),
14.2 (CH3). Found %: C, 66.85; H, 5.78; N, 8.11. For
C19H20N2O4 (340.14). Calculated %: C, 67.05; H, 5.92;
N, 8.23.
EXPERIMENTAL
General. The boiling point range of the petroleum ether
used was 40–60°C. Thin-layer chromatography was carried
out on TLC silica gel 60 F254 plastic plates (E. Merck, layer
thickness 0.2 mm). 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
General procedures for preparation (2-arylquinazolin-4-
yloxy) acetic acid 6a–b.
To a solution ester 5a–b
(1.0 mmol) in methyl alcohol (30 mL) was added
potassium hydroxide (0.112 g, 2.0 mmol) solution in
10 mL H2O. The reaction mixture was stirred at room
temperature for 4 h until complete consumption of the
ester (monitored by thin-layer chromatography). The
reaction mixture was diluted with water and acidified by
concentrated HCl. The separated precipitate was filtered
off, washed several times with water, and dried. The
resultant white product was crystallized from ethanol to
give the carboxylic acid 6a–b in pure state.
are uncorrected. H and 13C NMR spectra were recorded
1
at 300 and 75.5 MHz, respectively (Bruker AC 300) in
CDCl3 and DMSO solution with tetramethylsilane as an
internal standard. The NMR analyses were performed at
Organic Chemistry Department of Masaryk University,
Brno, Czech Republic. Elemental analyses were per-
formed on a Flash EA-1112 instrument at the Microanalyt-
ical Laboratory, Faculty of Science, Suez Canal
University, Ismailia, Egypt. 2-Arylquinazolin-4(3H)-ones
(4a–b) were prepared according to the method described
[17–19].
(2-Phenylquinazolin-4-yloxy) acetic acid (6a).
White
crystals 0.18 g (64%) 6a, M.p.: 180–181°C; 1H NMR
(300 MHz, CDCl3): δ = 13.22 (1H, bs, OH), 8.50–8.47
(2H, m, Ar–H), 8.22 (1H, d, J = 6.0 Hz, Ar–H), 8.00
(2H, s, Ar–H), 7.71–7.67 (1H, m, Ar–H), 7.56–7.54 (3H,
t, J = 3.0 Hz, Ar–H), 5.24 (2H, s, OCH2); 13C NMR
spectrum (75 MHz, CDCl3): δ = 169.9 (C═O), 166.1,
159.0, 151.86, 137.6, 135.0, 131.4, 129.1, 128.5, 128.2,
127.9, 123.7, 114.7(C–Ar), 63.9 (OCH2). Found %: C,
67.81; H, 4.89; N, 9.73. For C16H14N2O3 (282.10).
Calculated %: C, 68.07; H, 5.00; N, 9.92.
General procedures for preparation of ethyl 2-(2-
arylquinazolin-4-yloxy) acetate 5a–b.
To a solution of
quinazoline 4-one derivatives 4a–b (22.5 mmol) in DMF
(30 mL) were added successively potassium carbonate
(3.1 g, 22.5 mmol) and ethyl chloroacetate (3.7 mL,
30 mmol). The reaction mixture was stirred at room
temperature for 24 h. The reaction mixture was filtered
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Month 2018
Synthesis and Antimicrobial Activity of Some O-Substituted Amino Acid
Coupled Quinazoline Derivatives
[2-(4-Methoxy-phenyl) quinazolin-4-yloxy] acetic acid
(6b).
11.25. For C20H19N3O4 (365.14). Calculated %: C,
65.74; H, 5.24; N, 11.50.
Methyl 4-(2-(2-phenylquinazolin-4-yl)oxy) acetylamino
White crystals 0.19 g (60%) 6b, M.p.: 200–
1
201°C; H NMR (300 MHz, CDCl3): δ = 8.42–8.40 (2H,
m, Ar–H), 8.14–8.01 (4H, m, Ar–H), 7.12–7.06 (2H, m,
Ar–H), 5.21 (2H, s, OCH2), 3.85 (3H, s, OCH3). Found
%: C, 65.23; H, 5.01; N, 8.86. For C17H16N2O4 (312.11).
Calculated %: C, 65.38; H, 5.16; N, 8.97.
butanoate (7c).
White crystals 0.43 g (54%) 7c, M.p.:
1
115–116°C; H NMR (300 MHz, CDCl3): δ = 8.55 (2H,
t, J = 4.0 Hz, Ar–H), 8.28 (1H, d, J = 12.0 Hz, Ar–H),
8.02 (1H, d, J = 8.0 Hz, Ar–H), 7.89–7.85 (1H, t,
J = 8.0 Hz, Ar–H), 7.60–7.56 (1H, m, Ar–H), 7.49 (3H,
s, Ar–H), 6.85 (1H, s, NH), 5.22 (2H, s, OCH2), 3.57
(3H, s, OCH3), 3.45–3.40 (2H, q, J = 8.0 Hz, CH2),
2.37–2.34 (2H, t, J = 8.0 Hz, CH2), 1.89–1.86 (2H, m,
CH2); 13C NMR spectrum (75 MHz, CDCl3): δ = 172.9
(C═O), 167.6 (C═O), 165.7, 159.3, 152.0, 137.3, 134.0,
130.9, 128.9, 128.5, 128.0, 127.2, 123.0, 114.7 (C–Ar),
65.5 (OCH2), 51.8 (OCH3), 45.2 (CH2), 31.2 (CH2), 23.7
(CH2). Found %: C, 66.37; H, 5.32; N, 10.85. For
C21H21N3O4 (379.15). Calculated %: C, 66.48; H, 5.58;
General procedures for preparation of methyl 2-(2-(2-
arylquinazolin-4-yl)oxy) acetylamino alkanoates 7–8(a–f) by
DCC coupling method.
To a cold solution (ꢀ5°C) of
amino acid ester hydrochloride (4.4 mmol) in acetonitrile
(40 mL) containing triethylamine (0.62 mL, 4.4 mmol),
HOBt (0.59 g, 4.4 mmol), 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 work-up
procedure was repeated several times to ensure the
complete removal of dicyclohexylurea. The ethyl acetate
solution of the crude product 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 to
N, 11.08.
Methyl 2-(2-(2-phenylquinazolin-4-yl)oxy) acetylamino
propanoate (7d). White crystals 0.56 g (71%) 7d, M.p.:
1
230–231°C; H NMR (300 MHz, CDCl3): δ = 8.59–8.56
(2H, m, Ar–H), 8.24 (1H, d, J = 9.0 Hz, Ar–H), 8.06
(1H, d, J = 9.0 Hz, Ar–H), 7.90 (1H, t, J = 9.0 Hz,
Ar–H), 7.61 (1H, t, J = 9.0 Hz, Ar–H), 7.52–7.50 (3H,
m, Ar–H), 7.07 (1H, d, J = 6.0 Hz, NH), 5.30 (1H, d,
J = 15.0 Hz, OCH2), 5.20 (1H, d, J = 15.0 Hz, OCH2),
4.79–4.69 (1H, m, CH), 3.74 (3H, s, OCH3), 1.47 (3H, d,
J = 6.0 Hz, CH3); 13C NMR spectrum (75 MHz, CDCl3):
δ = 173.1 (C═O), 167.2 (C═O), 165.2, 159.7, 152.3,
137.4, 134.1, 130.8, 128.8, 128.5, 128.3, 127.0, 122.9,
114.6 (C–Ar), 65.2 (OCH2), 52.6 (OCH3), 47.9 (NHCH),
18.5 (CH3). Found: C, 65.62; H, 5.13; N, 11.35. For
C20H19N3O4 (365.14). Calculated %: C, 65.74; H, 5.24;
give compound 7–8(a–f).
Methyl 2-(2-(2-phenylquinazolin-4-yl)oxy) acetylamino
acetate (7a).
White crystals 1.12 g (73%) 7a, M.p.:
1
140–141°C; H NMR (300 MHz, CDCl3): δ = 8.73 (1H,
t, J = 6.0 Hz, NH), 8.53–8.50 (2H, m, Ar–H), 8.33
(1H, d, J = 9.0 Hz, Ar–H), 8.00–7.98 (2H, m, Ar–H),
7.71–7.67 (1H, m, Ar–H), 7.66–7.53 (3H, m, Ar–H),
5.22 (2H, s, OCH2), 3.96 (2H, d, J = 6.0 Hz, NHCH2),
3.60 (3H, s, OCH3); 13C NMR spectrum (75 MHz,
CDCl3): δ = 173.1 (C═O), 168.0 (C═O), 166.0, 159.2,
151.9, 137.6, 133.9, 131.3, 129.0, 128.6, 128.0, 127.1,
124.2, 114.9 (C–Ar), 65.2 (OCH2), 52.2 (OCH3), 40.9
(NHCH2). Found %: C, 64.82; H, 4.76; N, 11.84. For
C19H17N3O4 (351.12). Calculated %: C, 64.95; H, 4.88;
N, 11.96.
N, 11.50.
Methyl 2-(2-(2-phenylquinazolin-4-yl)oxy) acetylamino
3-methylbutanoate (7e). White crystals 0.69 g (66%) 7e,
M.p.: 185–186°C; 1H NMR (300 MHz, CDCl3):
δ = 8.58–8.55 (2H, m, Ar–H), 8.22 (1H, d, J = 6.0 Hz,
Ar–H), 8.06 (1H, d, J = 9.0 Hz, Ar–H), 7.87 (1H, t,
J = 6.0 Hz, Ar–H), 7.59–7.57 (1H, m, Ar–H), 7.53–7.49
(3H, m, Ar–H), 6.96 (1H, d, J = 9.0 Hz, NH), 5.35
(1H, d, J = 15.0 Hz, OCH2), 5.19 (1H, d, J = 15.0 Hz,
OCH2), 4.71–4.67 (1H, q, J = 3.0 Hz, CH), 3.71 (3H, s,
OCH3), 2.25–2.16 (1H, m, CH), 0.91 (3H, d, J = 6.0 Hz,
CH3), 0.85 (3H, d, J = 6.0 Hz, CH3); 13C NMR spectrum
(75 MHz, CDCl3): δ = 172.1 (C═O), 167.6 (C═O),
165.2, 159.4, 152.3, 137.3, 134.1, 130.8, 129.0, 128.5,
128.3, 127.3, 122.9, 114.6 (C–Ar), 65.4 (OCH2), 56.8
(OCH3), 52.2 (NHCH), 31.4 (CH), 18.8 (CH3), 18.7
(CH3). Found %: C, 67.03; H, 5.69; N, 10.56. For
C22H23N3O4 (393.17). Calculated %: C, 67.16; H, 5.89;
Methyl 3-(2-(2-phenylquinazolin-4-yl)oxy) acetylamino
propanoate (7b). White crystals 1.48 g (92%) 7b, M.p.:
175–176°C; 1H NMR (300 MHz, CDCl3): δ = 8.55–
8.51 (2H, m, Ar–H), 8.19 (1H, d, J = 9.0 Hz, Ar–H),
8.00 (1H, d, J = 9.0 Hz, Ar–H), 7.86–7.81 (1H, t,
J = 9.0 Hz, Ar–H), 7.50–7.47 (4H, m, Ar–H), 7.20 (1H,
s, NH), 5.45 (2H, s, OCH2), 3.64–3.58 (2H, q,
J = 6.0 Hz, CH2), 3.52 (3H, s, OCH3), 2.57–2.53 (2H, t,
J = 6.0 Hz, CH2); 13C NMR spectrum (75 MHz,
CDCl3): δ = 172.9 (C═O), 167.9 (C═O), 165.2, 159.6,
152.2, 137.3, 134.0, 130.8, 128.9, 128.6, 128.4, 127.1,
123.1, 114.8 (C–Ar), 65.3 (OCH2), 51.3 (OCH3), 34.5
(NHCH2), 33.5 (CH2). Found %: C, 65.54; H, 5.03; N,
N, 10.68.
Methyl 2-(2-(2-phenylquinazolin-4-yl)oxy) acetylamino
4-methylpentanoate (7f). White crystals 0.55 g (61%) 7f,
1
M.p.: 130–131°C; H NMR (300 MHz, CDCl3): δ = 8.70
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. Megahed, W. Fathalla, and A. A. Alsheikh
Vol 000
(1H, d, J = 9.0 Hz, NH), 8.52–8.49 (2H, m, Ar–H), 8.25
(1H, d, J = 9.0 Hz, Ar–H), 7.98–7.96 (2H, m, Ar–H),
7.70–7.65 (1H, m, Ar–H), 7.54–7.51 (3H, m, Ar–H),
5.25 (1H, d, J = 12.0 Hz, OCH2), 5.15 (1H, d,
J = 15.0 Hz, OCH2), 4.45–4.35 (1H, m, NHCH), 3.58
(3H, s, OCH3), 1.64–1.44 (1H, m, CH2, CH), 0.78–0.73
(6H, m, CH3); 13C NMR spectrum (75 MHz, CDCl3):
δ = 173.2 (C═O), 167.7 (C═O), 166.2, 159.1, 151.8,
137.6, 134.8, 131.3, 128.9, 128.6, 128.0, 127.6, 123.1,
114.8 (C–Ar), 65.2 (OCH2), 52.3 (OCH3), 50.4 (NHCH),
33.8 (CH), 24.9 (CH2), 23.1 (CH3), 21.6 (CH3). Found
%: C, 67.55; H, 6.08; N, 10.26. For C23H25N3O4
(407.18). Calculated %: C, 67.80; H, 6.18; N, 10.31.
128.0, 126.5, 122.9, 114.4, 113.9 (C–Ar), 65.6 (OCH2),
55.2 (OCH3), 51.5 (OCH3), 45.3 (CH2), 31.2 (CH2), 23.7
(CH2). Found %: C, 64.37; H, 5.49; N, 10.06. For
C22H23N3O5 (409.16). Calculated %: C, 64.54; H, 5.66;
N, 10.26.
Methyl
2-(2-(2-(4-methoxyphenyl)quinazolin-4-yl)oxy)
acetylamino propanoate (8d).
White crystals 0.67 g
(58%) 8d, M.p.: 230–231°C; 1H NMR (300 MHz,
CDCl3): δ = 8.50 (2H, d, J = 9.0 Hz, Ar–H), 8.20–8.17
(1H, m, Ar–H), 7.99 (1H, d, J = 9.0 Hz, Ar–H), 7.69–
7.63 (1H, m, Ar–H), 7.57–7.51 (1H, t, J = 9.0 Hz, Ar–
H), 7.11 (1H, d, J = 9.0 Hz, NH), 7.01 (1H, d,
J = 9.0 Hz, Ar–H), 5.27 (1H, d, J = 15.0 Hz, OCH2),
5.17 (1H, d, J = 15.0 Hz, OCH2), 4.78–4.69 (1H, m,
CH), 3.89 (3H, s, OCH3), 3.73 (3H, s, OCH3), 1.47 (3H,
d, J = 9.0 Hz, CH3); 13C NMR spectrum (75 MHz,
CDCl3): δ = 173.1 (C═O), 167.3 (C═O), 165.6, 162.1,
159.3, 152.1, 133.9, 130.2, 128.8, 127.9, 126.6, 122.9,
114.3, 113.9 (C–Ar), 65.2 (OCH2), 55.4 (OCH3), 52.6
(OCH3), 47.8 (NHCH), 18.5 (CH3). Found %: C, 63.73;
H, 5.28; N, 10.56. For C21H21N3O5 (395.15). Calculated
%: C, 63.79; H, 5.35; N, 10.63.
Methyl
2-(2-(2-(4-methoxyphenyl)quinazolin-4-yl)oxy)
acetylamino acetate (8a).
White crystals 1.20 g (98%)
8a, M.p.: 120–121°C; 1H NMR (300 MHz, CDCl3):
δ = 8.73 (1H, s, NH), 8.45 (2H, d, J = 9.0 Hz, Ar–H),
8.28 (1H, d, J = 9.0 Hz, Ar–H), 7.94 (2H, d, J = 3.0 Hz,
Ar–H), 7.65–7.60 (1H, m, Ar–H), 7.06 (2H, d,
J = 9.0 Hz, Ar–H), 5.19 (2H, s, OCH2), 3.97 (2H, d,
J = 3.0 Hz, NHCH2), 3.85 (3H, s, OCH3), 3.61 (3H, s,
OCH3); 13C NMR spectrum (75 MHz, CDCl3): δ = 172.5
(C═O), 168.1 (C═O), 165.8, 162.1, 159.1, 151.9, 134.7,
130.3, 130.2, 127.8, 127.0, 124.2, 114.5, 114.3 (C–Ar),
65.2 (OCH2), 55.7 (OCH3), 52.2 (OCH3), 40.9 (NHCH2).
Found %: C, 62.83; H, 4.86; N, 10.93. For C20H19N3O5
(381.13). Calculated %: C, 62.99; H, 5.02; N, 11.02.
Methyl
2-(2-(2-(4-methoxyphenyl)quinazolin-4-yl)oxy)
acetylamino 3-methylbutanoate (8e). White crystals 1.13 g
(72%) 8e, M.p.: 240–241°C; 1H NMR (300 MHz,
CDCl3): δ = 8.53–8.50 (2H, d, J = 9.0 Hz, Ar–H), 8.20–
8.17 (1H, d, J = 9.0 Hz, Ar–H), 8.02–7.99 (1H, d,
J = 9.0 Hz, Ar–H), 7.88–7.85 (1H, t, J = 9.0 Hz, Ar–H),
7.58–7.53 (1H, t, J = 9.0 Hz, Ar–H), 7.02–6.99 (2H, d,
J = 9.0 Hz, Ar–H), 6.96 (1H, d, J = 9.0 Hz, NH), 5.33
(1H, d, J = 15.0 Hz, OCH2), 5.17 (1H, d, J = 15.0 Hz,
OCH2), 4.70–4.66 (1H, q, J = 3.0 Hz, CH), 3.89 (3H, s,
OCH3), 3.71 (3H, s, OCH3), 2.24–2.14 (1H, m, CH),
0.90 (3H, d, J = 6.0 Hz, CH3), 0.84 (3H, d, J = 6.0 Hz,
CH3); 13C NMR spectrum (75 MHz, CDCl3): δ = 172.1
(C═O), 167.6 (C═O), 165.1, 162.0, 159.5, 152.4, 134.0,
130.2, 129.9, 128.0, 126.6, 122.8, 114.3, 113.8 (C–Ar),
65.3 (OCH2), 56.7 (OCH3), 55.4 (OCH3), 52.2 (NHCH),
31.4 (CH), 18.8 (CH3), 7.7 (CH3). Found %: C, 65.06;
H, 5.87; N, 9.62. For C23H25N3O5 (423.18). Calculated
%: C, 65.24; H, 5.95; N, 9.92.
Methyl
3-(2-(2-(4-methoxyphenyl)quinazolin-4-yl)oxy)
acetylamino propanoate (8b).
White crystals 0.65 g
(95%) 8b, M.p.: 125–126°C; 1H NMR (300 MHz,
CDCl3): δ = 8.50 (2H, d, J = 9.0 Hz, Ar–H), 8.20–8.13
(1H, t, J = 9.0 Hz, Ar–H), 7.99 (1H, d, J = 9.0 Hz,
Ar–H), 7.86–7.84 (1H, m, Ar–H), 7.57–7.51 (1H, t,
J = 9.0 Hz, Ar–H), 7.02 (1H, bs, NH), 6.99 (2H, d,
J = 9.0 Hz, Ar–H), 5.18 (2H, s, OCH2), 3.90 (3H, s,
OCH3), 3.66–3.60 (2H, q, J = 6.0 Hz, CH2), 3.54 (3H, s,
OCH3), 2.58–2.54 (2H, t, J = 6.0 Hz, CH2); 13C NMR
spectrum (75 MHz, CDCl3): δ = 172.9 (C═O), 167.8
(C═O), 165.0, 162.1, 159.4, 152.3, 133.9, 130.1, 128.9,
127.9, 126.5, 122.9, 114.4, 113.9 (C–Ar), 65.3 (OCH2),
55.4 (OCH3), 51.7 (OCH3), 34.5 (NHCH2), 33.5 (CH2).
Found %: C, 63.55; H, 5.21; N, 10.48. For C21H21N3O5
(395.15). Calculated %: C, 63.79; H, 5.35; N, 10.63.
Methyl
2-(2-(2-(4-methoxyphenyl)quinazolin-4-yl)oxy)
acetylamino 4-methylpentanoate (8f).
White crystals
1
1.42 g (54%) 8f, M.p.: 125–126°C; H NMR (300 MHz,
CDCl3): δ = 8.67 (1H, d, J = 6.0 Hz, NH), 8.45 (2H, d,
J = 9.0 Hz, Ar–H), 8.21 (1H, d, J = 9.0 Hz, Ar–H), 7.94
(2H, d, J = 3.0 Hz, Ar–H),7.66–7.60 (1H, m, Ar–H),
7.05 (2H, d, J = 9.0 Hz, Ar–H), 5.23 (1H, d,
J = 15.0 Hz, OCH2), 5.12 (1H, d, J = 15.0 Hz, OCH2),
4.44–4.32 (1H, m, NHCH), 3.85 (3H, s, OCH3), 3.58
(3H, s, OCH3), 1.64–1.45 (3H, m, CH2, CH), 0.79–0.74
(6H, m, CH3); 13C NMR spectrum (75 MHz, CDCl3):
δ = 173.2 (C═O), 167.7 (C═O), 166.0, 162.0, 159.0,
151.9, 134.7, 130.2, 129.9, 127.8, 127.1, 122.9, 114.6,
114.2 (C–Ar), 65.1(OCH2), 55.8 (OCH3), 52.3 (OCH3),
Methyl
4-(2-(2-(4-methoxyphenyl)quinazolin-4-yl)oxy)
acetylamino butanoate (8c). White crystals 0.73 g (55%)
8c, M.p.: 110–111°C; 1H NMR (300 MHz, CDCl3):
δ = 8.49 (2H, d, J = 8.0 Hz, Ar–H), 8.24 (1H, d,
J = 8.0 Hz, Ar–H), 7.98–7.96 (1H, m, Ar–H), 7.85–7.81
(1H, m, Ar–H), 7.55–7.51 (1H, m, Ar–H), 6.99 (2H, d,
J = 12.0 Hz, Ar–H), 6.83 (1H, bs, NH), 5.19 (2H, s,
OCH2), 3.88 (3H, s, OCH3), 3.56 (3H, s, OCH3), 3.45–
3.40 (2H, q, J = 8.0 Hz, CH2), 2.37–2.34 (2H, t,
J = 8.0 Hz, CH2), 1.90–1.86 (2H, m, CH2); 13C NMR
spectrum (75 MHz, CDCl3): δ = 172.7 (C═O), 167.4
(C═O), 165.3, 162.1, 159.4, 152.2, 133.9, 130.2, 129.6,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Synthesis and Antimicrobial Activity of Some O-Substituted Amino Acid
Coupled Quinazoline Derivatives
50.4 (NHCH), 24.6 (CH2), 23.2 (CH), 21.6 (2CH3). Found
%: C, 65.77; H, 6.01; N, 9.34. For C24H27N3O5 (437.20).
Calculated %: C, 65.89; H, 6.22; N, 9.60.
Fukui functions over the oxygen and nitrogen atoms were
taken into account. For a finite system such as an
inhibitor molecule, when the molecule has a tendency to
accept electrons, it has the nucleophilic attack index (f þk Þ,
and the index for the electrophilic attack (f ꢀk Þ indicates
that the molecule has a tendency to denote electrons. From
Table 1, the highest value of f ꢀk locates on the N3 atom,
which is ꢀ0.041, and it suggests that the electrophilic
attack on this atom is also preferred.
Biological activity materials and methods.
Bacterial strain.
Clinical isolated of 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 isolates of one clinical culture
(C. albicans) were used to evaluate the antifungal activity
of the synthesized compounds.
Reference therapeutic drugs.
Three antibiotic drugs
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were used in this work
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2. Erythromycin (15 μg)
3. Novobiocin (30 μg)
The synthetic compounds dissolved in DMSO were
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concentrations (30, 15, and 100 μg per disc) against
two reference bacterial strains (E. coli NCMB 11943;
S. aureus NCMB 6571) and one clinical culture
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bacterial strains, and potato dextrose agar was used for
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negative controls (DMSO-loaded discs) and positive
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the clear zone diameter after incubation at 37°C for
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24 h for bacteria and at 30°C for 48 h for Candida.
Quantum chemistry computations (neutral fragments).
The computations in this work were performed with a
MOLPRO program package [29,30]. The initial structure of
4a compound was edited by an Avogadro package [31].
The structure was optimized using at the DFT(B3LYP)
(Becke three parameters hybrid Lee–Yang–Parr) and
STO-3G basis set (Slater-type orbital with three Gaussian
primitive functions). The optimized geometric structure
of 4a compound calculated using DFT(B3LYP)/STO-3G
level of theory is presented in Figure 1.
Fukui functions.
The Fukui functions for all atoms
within molecule 4a were calculated at the DFT(B3LYP)/
STO-3G level of theory using Mulliken population
analysis. By applying finite difference approximation, the
Fukui functions can be written as [32] follows:
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Tamney, E. ARKIVOC 2017, iv, 104.
f þk ¼ qkðN þ 1Þ ꢀ qkðNÞ ðfor nucleophilic attackÞ;
f ꢀk ¼ qkðNÞ ꢀ qkðN ꢀ 1Þ ðfor electrophilic attackÞ:
Herein, qk(N), qk(N + 1), and qk(N ꢀ 1) are defined as
the atomic charges of the neutral, anionic, and cationic
species, respectively. The nucleophilic and electrophilic
Fukui functions for all atoms of the 4a molecule are
presented in Table 1. For simplicity, only the charges and
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