Synthesis of quinazolindionyl amino acid and hydrazone derivatives as possible antitumour agents

Article abstract of DOI:10.24820/ark.5550190.p010.310

A series of 1-ethyl-2,4-dioxo-(1H,3H)-quinazolin-3-yl amino acid and hydrazone derivatives were synthesized and tested for their antitumor activity. The alcohol and acid derivatives of quinazolindione were conjugated with the amino acid derivatives at N-3 site via ester or amide bonds by carbodiimide and azide methods. The carbodiimide-mediated amide and esterification steps were performed in the presence of HOBt or DMAP respectively otherwise the side-products N-acyl urea derivatives are formed, instead of the desired derivatives. Nine compounds exhibited encouraging antitumor activity against human liver carcinoma cell line (HepG2).

Full text of DOI:10.24820/ark.5550190.p010.310

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Arkivoc 2018, part iii, 20-35
Organic Chemistry
Synthesis of quinazolindionyl amino acid and hydrazone derivatives as possible
antitumour agents
A. Aboelmagd,*a Ezzeldin M. S. Salem,a Ibrahim A. I. Ali,a and Mohamed S. Gomaab
aDepartment of Chemistry, Faculty of Science, Suez Canal University, Ismailia, 41522, Egypt
bDepartment of Medicinal Chemistry, Faculty of Pharmacy, Suez Canal University, Ismailia, 41522, Egypt
Email: ahmedaelmagd@gmail.com
Received 08-23-2017
Accepted 10-22-2017
Published on line 11-26-2017
Abstract
A series of 1-ethyl-2,4-dioxo-(1H,3H)-quinazolin-3-yl amino acid and hydrazone derivatives were synthesized
and tested for their antitumor activity. The alcohol and acid derivatives of quinazolindione were conjugated
with the amino acid derivatives at N-3 site via ester or amide bonds by carbodiimide and azide methods. The
carbodiimide-mediated amide and esterification steps were performed in the presence of HOBt or DMAP
respectively otherwise the side-products N-acyl urea derivatives are formed, instead of the desired
derivatives. Nine compounds exhibited encouraging antitumor activity against human liver carcinoma cell line
(HepG2).
OH
O
O
N
O
N
O
N
H
N
O
R
OCH3
N
N
N
O
O
R
N
O
O
O
O
CH3
CH3
CH3
R2
R1
O
N
H
N
N
N
H
O
O
CH3
Keywords: Amino acids, quinazolindione, carbodiimide and azide coupling methods, hydrazones, antitumour
activity
DOI: https://doi.org/10.24820/ark.5550190.p010.310
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Introduction
Cancer is one of the major causes of death in the developed nations.1-3 Chemotherapy with cytotoxic drugs is
one of the main approaches to dealing with established cancer.4,5 The main drawbacks of the current
chemotherapy of cancer are the severe toxic effects such as emesis and myelosuppression, in addition to the
lack of selectivity of the drugs against tumour cells as compared with normal cells.1, 6 Hence, search for newer
anticancer drugs is never-ending task. Quinazolines are one of the most studied moieties in cancer
chemotherapy.7-13 Recently, FDA has approved several quinazoline derivatives as antitumour drugs from past
15 years such as gefitinib, erlotinib, lapatinib and raltitrexed.14-18 It should be noted that a group of peptide-
antibiotics such as actinomycin D (Dactinomycin) and bleomycin has been reported as antitumour agents.19, 20
Moreover, in literature it is established that anticancer effects have been shown with various hydrazones.21-23
Procarbazine, N-isopropyl-4-[(2-methylhydrazino)methyl]-benzamide, is one of the antitumour compounds
used in clinical practice.24
Based upon the afore-mentioned data, the present manuscript deals with the synthesis of a series of novel
compounds containing quinazolindione moiety conjugated with amino acid and hydrazone residues, to
evaluate their antitumour action. The amino acids used are selected to contain different physiologically active
side-chains such as hydroxyl, phenolic, heterocyclic, sulphur-containing and alkyl groups (serine, tyrosine,
tryptophan methionine, glycine, and leucine respectively). The synthesized derivatives include esters, free
acid, hydrazides and hydrazones (Schemes 1-3). The newly synthesized derivatives were screened for their
antitumour activity against liver carcinoma cell line (HepG2) (Tables 1).
Results and Discussion
25
The key compound 3-(2-hydroxyethyl)-2,4-dioxo(1H,3H)quinazoline 1 is a suitable scaffold for conjugation
with amino acid derivatives at N-3 position via amide and ester bonds (Schemes 1-3). Prior to derivatization of
1, the reactive N-1 site was protected by alkylation with ethyl iodide to yield the N-1 ethyl derivative 2 to avoid
the possible side-reactions that might occur.
Attachment of amino acids to quinazoline nucleus via amide bond required conversion of hydroxyethyl
derivative 2 to the corresponding acid 3 and ester 4 (Scheme 1).
Accordingly, compound 2 was oxidized with alkaline potassium permanganate to afford the corresponding
free acid 3. Esterification of 3 either with CH3OH / SOCl2 or with (CH3)2SO4 / K2CO3 yielded the methyl ester 4 in
64% and 69% yields respectively. 1H and 13C NMR spectra of acid 3 and ester 4 exhibited the presence of their
respective hydrogens and carbons in their expected trivial positions. Hydrazide 5 was prepared in 80% yield by
1
boiling the methyl ester 4 in methanol with six-fold excess hydrazine hydrate. The H NMR spectrum of
hydrazide derivative 5 showed new signals characteristic to the hydrazide group at 9.25 and 4.21 ppm of NH
and NH2 respectively.
The glycine methyl ester derivative 6a was synthesized by two different routes i.e. the azide and
carbodiimide methods. In the first procedure, the azide obtained from hydrazide 5 by treatment with nitrous
acid at 0 oC, reacted directly without isolation, with glycine methyl ester to afford the quinazolindione glycine
methyl ester derivative 6a in 47% yield. The reaction was carried out at low temperature to avoid Curtius
rearrangement of the azide to the corresponding isocyanate.26 On the other hand, when the acid 3 was
coupled with glycine methyl ester hydrochloride in the presence of dicyclohexyl-carbodiimide DCC, and
triethyl amine in acetonitrile the isolated product was 1-(1-ethyl-2,4-dioxo-(1H,3H)-quinazolin-3-ylacetyl)-1,3-
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dicyclohexyl urea (7) instead of desired glycine methyl ester derivative 6a. The structure of the by-product N-
1
13
acyl urea derivative 7 was elucidated by H NMR, C NMR and elemental analysis. However, pure sample of
the desired derivative 6a was obtained solely in a relatively higher yield (59%) when the reaction was repeated
in the presence of DCC / HOBt. The additive HOBt was used to suppress the formation of the by-product N-
acyl urea derivative 7.27
OH
OH
O
O
N
a
N
N
H
O
N
O
1
H3C
2
b
O
N
H
N
N
N
O
N
O
O
O
OH
N
7
H3C
O
h
i
O
O
N
O
H
H3C
3
N
c or d
N
OMe
6a
O
R
O
O
N
6
g
H3C
OMe
N
6a: Gly R = -H
6b: Ser R = -CH OH
6d: Met R = -CH CH SCH
2 2 3
6e: Leu R = -CH CH(CH )
O
O
O
2
2
2
3 2
6c: Trp R = -CH
N3
6f: Tyr R = -CH
2
N
OH
H3C
e
4
O
N
H
N
O
f
H3C
O
N
H
N
N
NH2
O
O
H3C
5
Scheme 1. Synthesis of 1-ethyl-2,4-dioxo-(1H,3H)-quinazolin-3-ylacetyl amino acid derivatives. Reagent and
conditions: a) EtI, anhydrous K2CO3, DMSO, 90 oC, 4 h; b) (i) KMnO4, Na2CO3, water 70 oC, 6 h; (ii) Conc. HCl to
pH 3; c) MeOH, SOCl2, r.t., 24 h; d) dimethyl sulfate, anhydrous K2CO3, acetone, reflux 5 h; e) N2H4.H2O, MeOH,
o
reflux 6 h; f) NaNO2 / HCl, AcOH, -5 C, stirring 0.5 h; g) HCl.H2NCH2CO2CH3, Et3N, in ethyl acetate, in
o
refrigerator 12 h and at r.t. 12 h; h) HCl.H2NCHRCO2CH3, Et3N, DCC in MeCN, 0 C 2 h and at r.t. overnight; i)
HCl.H2NCHRCO2CH3, Et3N, DCC, HOBt in MeCN, 0 oC 2 h and at r.t. overnight.
Accordingly, the remaining amino acid methyl ester derivatives 6b-f were prepared by coupling the acid 3
with the amino acid methyl esters (L-Ser-OMe, L-Trp-OMe, L-Met-OMe, L-Leu-OMe, and L-Tyr-OMe
respectively) by DCC / HOBt activation procedure in 45-56% yield. The chemical structures of 6a-f were
1
assigned by elemental analyses, H and 13C NMR. The 1H NMR spectra of amino acid derivatives 6a-f exhibited
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the following common data: multiplet signals between 6.85-6.35 ppm are of the NH protons of the peptide
bonds, multiplet signals between 4.97-4.11 ppm of the α-CH protons of the amino acids and singlet signals in
1
13
the range 3.80-3.65 ppm for the three protons of the ester OCH3 groups. H and C NMR signals for protons
and carbons of each side chain of the amino acids and quinazoline ring are reported in the experimental part.
Prior to the synthesis of the physiologically important hydrazones 10a-d, the hydrazide 9 was prepared by
hydrazinolysis of ester 6a (Scheme 2). We report herein, the synthesis of a series of quinazolindione glycyl
hydrazone derivatives 10a-d by condensation of the corresponding hydrazide 9 with some aromatic aldehydes
(benzaldehyde, anisaldehyde, 3-nitrobenzaldehyde and vanillin).
O
O
H
N
O
N
N
OMe
H
N
O
N
NH2
N
O
O
6a
O
H3C
H3C
b
5
a
O
O
H
N
N
N2H3
O
O
H
N
O
N
R1
R2
9
N
N
H3C
O
c
R1
N
O
R2
8
H3C
O
N
O
H
N
N
1
2
8a
: R = -H; R = -H
8b: R = -H; R = -OMe
8c
: R = -NO2; R = -H
8d: R = -OMe; R = -OH
N
N
H
1
2
O
O
1
2
1
2
10
1
2
10a: R = -H; R = -H
H3C
1
2
10b: R = -H; R = -OMe
1
2
10c: R = -NO2; R = -H
1
2
10d
: R = -OMe; R = -OH
Scheme 2. Synthesis of 1-ethyl-2,4-dioxo-(1H,3H)-quinazolin-3-ylacetyl hydrazone derivatives. Reagent and
conditions: a) ArCHO, EtOH, reflux, 3 h; b) N2H4.H2O, MeOH, reflux, 8 h; c) ArCHO, EtOH, reflux, 5 h.
On the other hand, the corresponding hydrazones, but without glycine, 8a-d have been analogously also
1
prepared from hydrazide 5 to study the effect of the amino acid on the antitumour potency. The H NMR of
the synthesized hydrazones (in DMSO-d6) showed that some protons exhibit two sets of signals for each
proton (NCH2CO and –N=CH of the hydrazones 8a-d and –NH-N, peptide NH, –N=CH, and α-CH2 of the
hydrazone derivatives 10a-d), which reveals the existence of an equilibrium mixture from cis/trans amide
conformers of the E-form (see experimental part). This conclusion is supported by previously published data
on similar compounds.28-31
As has been mentioned above, this study deals also with the synthesis of some amino acid
quinazolindionyl ethyl ester derivatives (Scheme 3). Surprisingly enough, trials to esterify phthalylglycine with
the alcohol derivative 2 with DCC in the presence of HOBt failed to give the desired ester 12 and instead, the
by-product N-phthalylglycyl dicyclohexyl urea 11 was obtained. However, the alcohol 2 underwent successful
acylation when reacted with acetic acid, benzoic acid or the sterically hindered phthalylglycine in the presence
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of DCC / DMAP to afford the corresponding esters 13a, 13b and 12 respectively. The structures of 11, 12, 13a
and 13b were confirmed by 1H NMR, 13C NMR, and elemental analyses (see the experimental part). Moreover,
the structures of 13a and 13b were further established by their synthesis by the classical methods i.e. by
acylation of 2 with acetic anhydride or benzoyl chloride in pyridine respectively. From these test experiments,
it seems that DMAP is superior additive to HOBt in DCC-mediated esterification of such type of compounds.
O
O
N
O
HN
N
O
11
d
O
N
O
N
O
O
O
R
OH
O
N
c
a
N
N
N
O
O
O
O
N
O
O
b
CH3
12
CH3
CH3
2
13
e
13a: R = -CH
13b: R = Ph
3
O
N
R
O
CH3
CH3
O
14a
14b
: Gly, R = -H
: Leu, R = -CH CH(CH )
N
N
H
O
2
3 2
CH3
O
14c
CH2
: Trp, R =
O
CH3
O
N
H
14
f
R
15a: Gly, R = -H
15b: Leu, R = -CH CH(CH )
O
2
3 2
NH3 Cl
N
15c: Trp, R = CH2
O
O
N
N
H
CH3
15
Scheme 3. Synthesis of amino acid 2-(1-ethyl-2,4-dioxo-(1H,3H)-quinazolin-3-yl)ethyl ester derivatives.
Reagent and conditions: a) phth-Gly, DCC, HOBt, CH2Cl2, r.t. 3 h; b) phth-Gly, DCC, DMAP, CH2Cl2 r.t. 3 h; c)
o
AcOH or PhCOOH, DCC, DMAP, CH2Cl2, r.t. 3 h; d) Ac2O or PhCOCl, pyridine, 0 C, 1 h; e) Boc-amino acid, DCC,
DMAP, CH2Cl2, r.t. 3 h; f) 1M HCl in ethyl acetate, r.t. 2 h.
Accordingly, t-butyloxycarbonyl-amino acid quinazolinyl ethyl esters 14a-b have been prepared in 63-67%
yields by acylation of the alcohol 2, with the corresponding Boc-amino acid (Gly, Leu, Trp) in the presence of
1
DCC / DMAP. The H NMR spectra of these derivatives showed a common singlet signal in the range between
1.39-1.26 ppm corresponding to the nine protons of the tert-butyloxy group -OC(CH3)3 and a broad signal
between 5.24-5.01 ppm attributed to the proton of the Boc-NH group. 13C NMR spectra displayed the
characteristic signals between 79.9-79.2 ppm of the tert-carbon -OC(CH3)3 and between 28.2-27.8 ppm of the
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carbons of the three methyl groups -OC(CH3)3, in addition to other signals corresponding to protons and
carbons of the different side chains of the amino acids and quinazoline ring which add further support to the
structures of the prepared esters (refer to the experimental part).
The Boc-groups were cleaved by the action of 1M HCl in ethyl acetate to yield the corresponding
1
13
hydrochloride salts 15a-c in 44-74% yield. H NMR and C NMR spectra of these compounds revealed the
disappearance of the characteristic signals of the Boc protons and carbons and instead the presence of broad
+
signals between 8.90-8.20 ppm for the three protons of NH3 group, alongwith other signals for protons and
carbons of the individual side chains of the corresponding amino acids (refer to the experimental part).
The synthesized quinazolindione derivatives were tested for their antiproliferative activity against human
liver carcinoma cell line (HepG2) where they showed promising activity (Table 1).
Table 1. In vitro antiproliferative activity of 1-ethyl-2,4-dioxo-(1H,3H)-quinazolin-3-ylacetyl amino acid and
hydrazone derivatives against human liver carcinoma cell line (HepG2)
Compound concentration
(µg/mL)
25 50
Surviving fraction
1.000 0.922 0.682 0.622
0.729 0.521 0.370 0.344 28.00
0.572 0.420 0.352 0.300 18.30
0.724 0.510 0.464 0.443 29.30
1.00 0.954 0.919 0.910
0.441 0.218 0.165 0.160
0.650 0.541 0.414 0.391 33.00
Compd.
IC50
12.5
100 (µg/mL)
1
2
5
6b
6c
6d
6e
>100
>100
9.68
6f
7
0.792 0.781 0.681 0.673
0.977 0.881 0.858 0.731
>100
>100
8a
8d
9
10b
12
0.850 0.575 0.355 0.350 33.70
0.759 0.271 0.254 0.336 19.10
1.000 0.696 0.546 0.380
0.714 0.621 0.514 0.460
>50
>50
0.593 0.436 0.263 0.305 19.70
13a
13b
14a
14b
14c
15a
15b
15c
0.886 0.750 0.741 0.727
0.746 0.654 0.638 0.400
0.986 0.772 0.707 0.630
0.500 0.455 0.341 0.386 12.50
0.923 0.712 0.692 0.420 >50
0.747 0.316 0.255 0.254 19.40
0.578 0.194 0.215 0.252 15.10
0.864 0.823 0.782 0.741
>100
>50
>100
>100
3.23
doxorubicin 0.248 0.275 0.360 0.344
It is clear that out of twenty seven screened novel synthesized compounds, nine compounds exhibited
IC50’s in the range of 9.68-33.7 µg/mL compared to the reference drug doxorubicin (IC50 3.23 µg/mL). The
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methionine methyl ester derivative 6d was found to be the most active synthesized compound with IC50 9.68
µg/mL. this derivative 6d could be considered as a lead compound for further optimization and development.
Conclusions
We hereby present the synthesis and preliminary antiproliferative activity study of a series of 1-ethyl-2,4-
dioxo-(1H,3H)-quinazolin-3-yl amino acid derivatives. The quinazolindione nucleus was connected with amino
acids by amide or ester bonds at N-3 site. The carbodiimide-mediated amide and esterification steps should be
performed in the presence of HOBt or DMAP respectively.
Since the quinazolindione amino acid methyl ester derivatives were obtained in the present study with
moderate yields by the azide or carbodiimide methods, other coupling procedures should be attempted with
the aim to get better yields. The synthesized compounds showed good activity against HepG2 cell line and the
results generated compound 6d (IC50 9.6 µg/mL) as a lead compound for further optimization and
development. Based up on the obtained promising anticancer results, it is necessary to extend this study for
the synthesis of a series of N3-quinazolindione amino acid esters bearing other different open side-chains.
Moreover, the synthesis of other hydrazones derived from aliphatic carbonyl compounds could afford novel
derivatives with enhanced anticancer action.
Experimental Section
General. Thin layer chromatography (TLC) was carried out on silica gel 60 F254 aluminium sheets (E. Merck,
layer thickness 0.2 mm) in the following solvent systems, S1: chloroform / methanol (95:5); S2:
chloroform/methanol (9:1); S3: ethyl acetate/petroleum ether (2:1); S4: ethyl acetate/petroleum ether (1:1).
The spots on thin layer plates were detected by UV lamp. Melting points were determined on a Buchi 510
melting-point apparatus. Elemental analyses were performed on a Flash EA-1112 instrument at the
1
13
Microanalytical Laboratory, Faculty of Science, Suez Canal University, Ismailia, Egypt. H and C NMR spectra
were measured on Bruker spectrometer operating at 300 and 75 MHz respectively, at microanalytical
laboratory, Cairo University, Giza, Egypt. The starting compounds 3-(2-hyd-roxyethyl)-2,4-di-oxo-(1H,3H)-
quinazoline 1 and 1-ethyl-3-(2-hydroxyeth-yl)-2,4-dioxo-(1H,3H)-quinazoline 2 were prepared according to the
described method in literature.25 Potential cytotoxicity of the newly synthesized compounds was tested
against human liver carcinoma cell line (HepG2) at pharmacology unit in cancer biology department at the
National Cancer Institute, Cairo University, Cairo.
1-Ethyl-2,4-dioxo-(1H,3H)-quinazolin-3-ylacetic acid (3). To a suspension of 2 (2.34 g, 10 mmol) in sodium
carbonate solution (1.05 g, in 25 mL water) KMnO4 solution (4.0 g in 25 mL water) was added. The reaction
o
mixture was heated on water bath at 70 C for 6 hrs. Afterwards, the MnO2 was filtered off and the cold
filtrate was acidified with conc. HCl to pH 3. The formed white ppt, after filtration, was washed with cold
water, and crystallized from aqueous ethanol to yield white crystals (1.81 g, 73%), Rf = 0.53(S2), mp 227-229 oC.
1H NMR (300 MHz, DMSO-d6): δ 13.00 (1H, brs, OH), 8.08 (1H, d, J 9.1 Hz, ArH), 7.84-7.78 (1H, t, J 9.1 Hz, ArH),
7.56 (1H, d, J 9.1 Hz, ArH), 7.35-7.30 (1H, t, J 9.1 Hz, ArH), 4.62 (2H, s, NCH2CO), 4.19-4.12 (2H, m, NCH2CH3),
1.24-1.15 (3H, m, NCH2CH3). 13C NMR (75 MHz, DMSO-d6): δ 169.2, 160.7, 149.62 (3CO), 139.2, 135.7, 128.1,
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122.8, 114.6, 114.4 (Ar-C), 42.3 (NCH2CO), 38.3 (NCH2CH3), 12.3 (NCH2CH3). Anal. Calcd. For C12H12N2O4
(248.23): C, 58.06; H, 4.87; N, 11.29; Found C, 58.16; H, 4.82; N, 11.44.
Methyl 1-ethyl-2,4-dioxo-(1H,3H)-quinazolin-3-ylacetate (4)
Method A. To a suspension of 3 (2.48 g, 10 mmol) in methanol (25 mL), thionyl chloride (0.8 mL, 11 mmol) was
added dropwise. The reaction mixture was stirred at room temperature for 24 hrs. Afterwards, the methanol
and excess thionyl chloride were evaporated under reduced pressure. The residue was dissolved in methanol
(10 mL) and evaporated under reduced pressure to get rid of residual thionyl chloride. Finally, the residue was
crystallized from ethyl acetate /petroleum ether to yield 4 as white crystals (1.69 g, 64%). Rf = 0.64(S3), mp 84-
86 oC.
Method B. A mixture of 3 (2.48 g, 10 mmol), anhydrous potassium carbonate (1.37 g) and methyl sulphate
(0.95 mL, 10 mmol) in acetone (25 mL) was heated under reflux for 5 hrs. The reaction mixture was poured
under stirring into ice-water mixture, and then the solid precipitate was filtered, washed with water and dried
in air. The crude product was crystallized from ethyl acetate /petroleum ether to yield 4 as white crystals (1.81
1
g, 69%). Rf = 0.64(S3), mp 83-86 oC. H NMR (300 MHz, CDCl3): δ 8.24 (1H, d, J 7.8 Hz, ArH), 7.72-7.66 (1H, t, J
7.8 Hz, ArH), 7.28-7.22 (2H, m, ArH), 4.85 (2H, s, NCH2), 4.23-4.16 (2H, m, NCH2CH3), 3.77 (3H, s, OCH3), 1.37-
1.33 (3H, t, J 7.2 Hz, NCH2CH3). 13C NMR (75 MHz, CDCl3): δ 168.4, 161.3, 150.1 (3CO), 139.6, 135.4, 129.3,
122.9, 115.4, 113.5 (Ar-C), 52.4 (OCH3), 42.3 (NCH2), 38.9 (NCH2), 12.5 (CH3). Anal. Calcd. For C13H14N2O4
(262.26): C, 59.54; H, 5.38; N, 10.68; Found C, 59.87; H, 5.58; N, 10.93.
1-Ethyl-2,4-dioxo-(1H,3H)-quinazolin-3-ylacetyl hydrazide (5). To a solution of 4 (2.0 g, 7.62 mmol) in
methanol (30 ml), hydrazine hydrate (3 ml, 48.0 mmol) was added. The reaction mixture was refluxed for 6
hrs, after cooling to room temperature the precipitated hydrazide was filtered off, washed with water and
ethanol followed by recrystallization from aqueous ethanol to give 5 as white crystals (1.61 g, 80%), Rf =
0.52(S2), mp 218-221 oC. 1H NMR (300 MHz, DMSO-d6): δ 9.25 (1H, s, NH), 8.07 (1H, d, J 7.5 Hz, ArH), 7.82-7.76
(1H, t, J 7.5 Hz, ArH), 7.53 (1H, d, J 7.5 Hz, ArH), 7.33-7.28 (1H, t, J 7.5 Hz, ArH), 4.51 (2H, s, NCH2), 4.21 (2H, s,
NH2), 4.17-4.10 (2H, m, NCH2CH3), 1.24-1.19 (3H, t, J 7.0 Hz, NCH2CH3). 13C NMR (75 MHz, DMSO-d6): δ 166.7,
161.4, 150.3 (3CO), 139.9, 135.9, 128.5, 123.1, 115.5, 114.8 (Ar-C), 42.8 (NCH2), 38.7 (NCH2), 12.8(CH3). Anal.
Calcd. For C12H14N4O3 (262.26): C, 54.96; H, 5.38; N, 21.36; Found C, 54.98; H, 5.67; N, 21.10.
1-Ethyl-2,4-dioxo-(1H,3H)-quinazolin-3-ylacetyl glycine methyl ester (6a)
Method A. Azide coupling method: To a cold solution (-5 oC) of hydrazide 5 (0.21g, 0.8 mmol) in acetic acid (6
ml), hydrochloric acid (5N, 3 ml), and water (25 ml), was added portionwise under stirring a cold solution (0 oC)
of sodium nitrite (0.07 g, 1.0 mmol) in water (3 ml). After stirring at the same temperature for 30 minutes, the
azide was extracted with cold ethyl acetate, and washed successively with cold water, 5% NaHCO3 and water.
After drying over anhydrous sodium sulphate, the azide was used without further purification in the next step.
Glycine methyl ester hydrochloride (0.11 g, 0.9 mmol), was stirred in ethyl acetate (30 mL) with triethyl amine
o
(0.2 ml) at 0 C for 20 minutes. The formed triethyl amine hydrochloride was filtered off and the filtrate was
added to the previously prepared cold dried solution of the azide. Afterwards the mixture was kept 12 hrs in
the refrigerator and then at room temperature for another 12 hrs. The reaction mixture was washed with 0.1N
HCl, water, 5% NaHCO3 and water then dried over anhydrous sodium sulphate. The solvent was evaporated in
vacuum and the residue was crystallized from ethyl acetate-petroleum ether to give 6a as white crystals (0.12
g, 47%) Rf = 0.23(S3), mp 199-202 oC.
o
Method B. DCC coupling method: To a cold solution (-5 C) of glycine methyl ester hydrochloride (0.55 g, 4.4
mmol) and triethyl amine (0.62 ml. 4.4 mmol) in acetonitrile (40 ml) 1-ethyl-2,4-dioxo-(1H,3H)-quinazolin-3-
ylacetic acid (3) (1.09 g, 4.4 mmol), HOBt (0.6 g, 4.4 mmol), and DCC (0.92 g, 4.4 mmol) were added
o
successively. The reaction mixture was stirred at 0 C for 2 hrs. and at room temperature overnight. The
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precipitated dicyclohexylurea (DCU) was filtered off and the filtrate was evaporated under reduced pressure.
The residue was extracted with ethyl acetate, filtered off from the remaining DCU, afterwards 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 to dryness and the remaining residue was crystallized from
ethyl acetate/petroleum ether to yield 1-ethyl-2,4-dioxo-(1H,3H)-quinazolin-3-ylacetyl glycine methyl ester
(6a) as white crystals (0.82 g, 58%), Rf = 0.23(S3), mp 201-203 oC. 1H NMR (300 MHz, CDCl3): δ 8.24 (1H, d, J 7.8
Hz, ArH), 7.71- 7.65 (1H, t, J 7.8 Hz, ArH), 7.27-7.21 (2H, m, ArH), 6.42 (1H, brs, NH), 4.83 (2H, s, NCH2), 4.24-
4.17 (2H, m, NCH2CH3), 4.11 (2H, d, J 5.1 Hz, NCH2), 3.75 (3H, s, OCH3), 1.38-1.33 (3H, t, J 7.2 Hz, NCH2CH3). 13C
NMR (75 MHz, CDCl3): δ 170.1, 167.0, 161.6, 150.3 (4CO), 139.7, 135.3, 129.4, 122.9, 115.5, 113.5 (Ar-C), 52.4
(OCH3), 44.0 (NCH2CO), 41.3 (NCH2CO), 39.0 (NCH2CH3), 12.5 (CH3). Anal. Calcd. For C15H17N3O5 (319.31): C,
56.42; H, 5.37; N, 13.16; Found C, 56.57; H, 5.43; N, 13.26.
o
1-(1-Ethyl-2,4-dioxo-(1H,3H)-quinazolin-3-ylacetyl)-1,3-dicyclohexyl urea (7). To a cold solution (-5 C) of
glycine methyl ester hydrochloride (0.55 g, 4.4 mmol) and triethyl amine (0.62 ml. 4.4 mmol) in acetonitrile (40
ml) 1-ethyl-2,4-dioxo-(1H,3H)-quinazolin-3-ylacetic acid (3) (1.09 g, 4.4 mmol), and DCC (0.92 g, 4.4 mmol)
o
were added successively. The reaction mixture was stirred at 0 C for 2 hrs. and at room temperature
overnight. The precipitated DCU was filtered off and the filtrate was evaporated under reduced pressure. The
residue was extracted with ethyl acetate, filtered off from the remaining DCU, afterwards 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 to dryness and the remaining residue was crystallized from
ethyl acetate/petroleum ether to yield 1-(1-ethyl-2,4-dioxo-(1H,3H)-quinazolin-3-ylacetyl)-1,3-dicyclohexyl
urea (7) as white crystals (1.43 g, 71%), Rf = 0.87(S2), mp 155-158 oC. 1H NMR (300 MHz, CDCl3): δ 8.24 (1H, d, J
7.8 Hz, ArH), 7.72-7.67 (1H, t, J 7.8 Hz, ArH), 7.42 (1H, d, J 6.3 Hz, NH), 7.29-7.20 (2H, m, ArH), 4.99 (2H, s,
NCH2), 4.24-4.17 (2H, m, NCH2CH3), 4.10-3.95 (1H, m, NCH), 3.80-3.62 (1H, m, NCH), 2.01-1.15 (23H, m, 10 CH2
cyclohexyl rings, NCH2CH3). 13C NMR (75 MHz, CDCl3): δ 166.9, 161.7, 153.3, 150.4 (4CO), 139.7, 135.4, 129.3,
122.9, 115.4, 113.5 (Ar-C), 56.4, 49.9 (2NCH-cyclohexyl rings), 44.0 (NCH2CO), 39.0 (NCH2CH3), 32.5, 30.6, 26.3,
25.4, 25.2, 24.7 (CH2-cyclohexyl rings), 12.5 (NCH2CH3). Anal. Calcd. For C25H34N4O4 (454.56): C, 66.06; H, 7.54;
N, 12.33; Found C, 66.19; H, 7.57; N, 12.51.
1-Ethyl-2,4-dioxo-(1H,3H)-quinazolin-3-ylacetyl amino acid methyl esters (6b-f). General method. To a cold
solution (-5 oC) of amino acid methyl ester hydrochloride (4.4 mmol) and triethyl amine (0.62 ml. 4.4 mmol) in
acetonitrile (40 ml) acid derivative 3 (1.09 g, 4.4 mmol), HOBt (0.6g, 4.4 mmol), and DCC (0.92 g, 4.4 mmol)
were added successively. The reaction mixture was treated as described above under the synthesis of the
glycine methyl ester derivative 6a (Method B).
1-Ethyl-2,4-dioxo-(1H,3H)-quinazolin-3-ylacetyl L-serine methyl ester (7b). White crystals (0.68 g, 45%), Rf =
o
1
0.15(S3), mp 213-216 C. H NMR (300 MHz, CDCl3): δ 8.20 (1H, d, J 7.8 Hz, ArH), 7.68- 7.63 (1H, t, J 7.9 Hz,
ArH), 7.26-7.19 (3H, m, ArH, NH), 4.90 (1H, d, Jgem 15.3 Hz, NCHCO), 4.78 (1H, d, Jgem 15.3 Hz, NCHCO), 4.65-
4.60 (1H, m, NCH), 4.340-4.25 (1H, brs, OH), 4.20-4.13 (2H, m, NCH2CH3), 3.93-3.85 (2H, m, CH2O), 3.74 (3H, s,
13
OCH3), 1.34-1.29 (3H, t, J 7.2 Hz, NCH2CH3). C NMR (75 MHz, CDCl3): δ 170.7, 167.0, 160.7, 147.0 (4CO),
139.6, 136.6, 129.2, 122.7, 115.1, 113.4 (Ar-C), 62.7 (OCH2), 54.9 (NCH), 52.4 (OCH3), 43.9 (NCH2CO), 38.8
(NCH2CH3), 12.4 (CH3). Anal. Calcd. For C16H19N3O6 (349.34): C, 55.01; H, 5.48; N, 12.03; Found C, 55.19; H,
5.45; N, 12.22.
1-Ethyl-2,4-dioxo-(1H,3H)-quinazolin-3-ylacetyl L-tryptophane methyl ester (6c). White crystals (1.11 g, 56%),
o
1
Rf = 0.36(S3), mp 118-120 C. H NMR (300 MHz, CDCl3): δ 8.43 (1H, brs, Ind-NH), 8.24 (1H, d, J 7.8 Hz, ArH),
7.67- 7.65 (1H, m, ArH), 7.53 (1H, d, J 7.8 Hz, ArH), 7.28-7.05 (6H, m, 5ArH, Ind-2-H), 6.54-6.80 (1H, d, J 8.1 Hz,
NH), 4.97-4.94 (1H, m, NCH), 4.82 (1H, d, Jgem 15.3Hz, NCHCO), 4.72 (1H, d, Jgem 15.3 Hz, NCHCO), 4.17-4.10
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(2H, m, NCH2CH3), 3.65 (3H, s, OCH3), 3.34 (2H, d, CH2), 1.34-1.29 (3H, t, J 7.1 Hz, NCH2CH3). 13C NMR (75 MHz,
CDCl3): δ 172.1, 166.8, 161.6, 150.3 (4CO), 139.6, 136.1, 135.2, 129.2, 127.5, 123.6, 122.8, 121.7, 119.3, 118.3,
115.4, 113.5, 111.2, 109.1 (Ar-C), 53.2 (NCH), 52.3 (OCH3), 43.8 (NCH2CO), 38.9 (NCH2CH3), 27.4 (CH2), 12.5
(CH3). Anal. Calcd. For C24H24N4O5 (448.47): C, 64.28; H, 5.39; N, 12.49; Found C, 64.56; H, 5.68; N, 12.28.
Ethyl-2,4-dioxo-(1H,3H)-quinazolin-3-ylacetyl L-methionine methyl ester (6d). White crystals (0.88 g, 51%), Rf
o
1
= 0.48(S3), mp 168-170 C. H NMR (300 MHz, CDCl3): δ 8.25 (1H, d, J 7.8 Hz, ArH), 7.71- 7.66 (1H, t, J 7.8 Hz,
ArH), 7.28-7.21 (2H, m, ArH), 6.54 (1H, d, J 7.5 Hz, NH), 4.90 (1H, d, Jgem 15.6 Hz, NCHCO), 4.76 (1H, d, Jgem 15.6
Hz, NCHCO), 4.76-4.71 (1H, m, NCH), 4.24-4.17 (2H, m, NCH2CH3), 3.76 (3H, s, OCH3), 2.56-2.51 (2H, m, SCH2),
2.19-2.00 (2H, m, CH2), 2.07 (3H, s, SCH3), 1.36-1.32 (3H, t, J 7.1 Hz, NCH2CH3). 13C NMR (75 MHz, CDCl3): δ
172.1, 166.7, 161.5, 150.3 (4CO), 139.6, 135.3, 129.4, 122.9, 115.5, 113.5 (Ar-C), 52.4 (OCH3), 51.7 (NCH), 44.1
(NCH2CO), 39.0 (NCH2CH3), 31.7 (SCH2), 29.8 (CH2), 15.4 (SCH3), 12.5 (CH3). Anal. Calcd. For C18H23N3O5S
(393.46): C, 54.95; H, 5.89; N, 10.68; S, 8.15; Found C, 55.19; H, 6.04; N, 10.41; S, 8.38.
Ethyl-2,4-dioxo-(1H,3H)-quinazolin-3-ylacetyl L-leucine methyl ester (6e). White crystals (0.78 g, 47%), Rf =
0.54(S3), mp 141-144 oC. 1H NMR (300 MHz, CDCl3): δ 8.23 (1H, d, J 8.1 Hz, ArH), 7.69-7.64 (1H, t, J 8.1 Hz, ArH),
7.26-7.20 (2H, m, ArH), 6.36 (1H, d, J 7.8 Hz, NH), 4.86 (1H, d, Jgem 15.3 Hz, NCHCO), 4.78 (1H, d, Jgem 15.3 Hz,
NCHCO), 4.71-4.64 (1H, m, NCH), 4.22-4.15 (2H, m, NCH2CH3), 3.72 (3H, s, OCH3), 1.71-1.53 (3H, m, CH2, CH),
1.36-1.32 (3H, t, J 7.1 Hz, NCH2CH3), 0.93 (6H, d, J 6.3 Hz, 2CH3). 13C NMR (75 MHz, CDCl3): δ 173.2, 166.6,
161.5, 150.3 (4CO), 139.6, 135.3, 129.3, 122.8, 115.5, 113.4 (Ar-C), 52.2 (OCH3), 50.9 (NCH), 43.9 (NCH2CO),
41.9 (NCH2CH3), 38.7 (CH), 24.7 (CH2), 22.6, 22.04 (2CH3), 12.5 (CH3). Anal. Calcd. For C19H25N3O5 (375.42): C,
60.79; H, 6.71; N, 11.19; Found C, 61.02; H, 6.97; N, 11.44.
Ethyl-2,4-dioxo-(1H,3H)-quinazolin-3-ylacetyl L-tyrosine methyl ester (6f). White crystals (0.93 g, 50%), Rf =
o
1
0.36(S3), mp 184-187 C. H NMR (300 MHz, CDCl3): δ 8.26 (1H, d, J 7.8 Hz, ArH), 7.72- 7.67 (1H, t, J 7.8 Hz,
ArH), 7.29-7.22 (2H, m, ArH), 6.96 (2H, d, J 8.4 Hz, ArH), 6.68 (2H, d, J 8.4 Hz, ArH), 6.35 (1H, d, J 7.8 Hz, NH),
4.90-4.84 (H, m, NCH), 4.84 (1H, d, Jgem 15.3 Hz, NCHCO), 4.75 (1H, d, Jgem 15.3 Hz, NCHCO), 4.22-4.16 (2H, m,
NCH2CH3), 3.73 (3H, s, OCH3), 3.09-3.05 (2H, m, CH2Ph), 1.35-1.26 (3H, t, J 7.2 Hz, NCH2CH3). 13C NMR (75 MHz,
CDCl3): δ 171.8, 166.6, 161.6 (3CO), 155.5 (Ar-C) 150.3 (CO), 139.6, 135.4, 130.4, 129.3, 126.7, 122.9, 115.5,
113.4 (Ar-C), 52.3 (OCH3), 49.1 (NCH), 44.0 (NCH2CO), 39.0 (NCH2CH3), 25.5 (CH2), 12.4 (CH3). Anal. Calcd. For
C22H23N3O6 (425.43): C, 62.11; H, 5.45; N, 9.88; Found C, 62.30; H, 5.72; N, 10.21.
General procedure for the synthesis of hydrazones (8a-d). A mixture of hydrazide 5 (0.3 g, 1.14 mmol) and
aromatic aldehyde (1.2 mmol) was refluxed in ethanol (20 ml) for 3 hours. After cooling to room temperature,
the resulting solid was filtered, washed with cold ethanol and recrystallized from aqueous ethanol.
1-Ethyl-2,4-dioxo-(1H,3H)-quinazolin-3-ylacetyl benzylidene hydrazone (8a). White crystals (0.36 g, 91%), Rf =
0.66(S1), mp 274-276 oC. 1H NMR (300 MHz, DMSO-d6): δ 11.67 (1H, s, NH), 8.22, 8.04 (1H, 2s, CH), 8.09 (1H, d,
J 8.1 Hz, ArH), 7.83-7.78 (1H, t, J 7.8 Hz, ArH), 7.76-7.65 (2H, m, ArH), 7.55 (1H, d, J 8.4 Hz, ArH), 7.50-7.39 (3H,
m, ArH), 7.35-7.30 (1H, t, J 7.5 Hz, ArH), 5.10, 4.70 (2H, 2s, NCH2CO), 4.19-4.10 (2H, m, NCH2CH3), 1.25-1.20
(3H, t, J 6.7 Hz, NCH2CH3). 13C NMR (75 MHz, DMSO-d6): δ 167.9, 160.8 149.7 (3CO), 144.0 (CH), 139.2, 135.6,
134.0, 129.9, 128.7, 128.1, 126.8, 122.7, 114.8, 114.3 (Ar-C), 42.3 (NCH2CO), 38.2 (NCH2CH3), 12.3 (CH3). Anal.
Calcd. For C19H18N4O3 (350.37): C, 65.13; H, 5.18; N, 15.99; Found C, 64.87; H, 5.16; N, 16.23.
1-Ethyl-2,4-dioxo-(1H,3H)-quinazolin-3-ylacetyl 4\-methoxybenzylidene hydrazone (8b). White crystals (0.42
o
1
g, 96%), Rf = 0.68(S1), mp 267-269 C. H NMR (300 MHz, DMSO-d6): δ 11.53 (1H, s, NH), 8.09 (1H, d, J 8.1 Hz,
ArH), 8.15, 7.98 (1H, 2s, CH), 7.83-7.78 (1H, t, J 7.9 Hz, ArH), 7.66 (1H, d, J 8.7 Hz, ArH), 7.55 (1H, d, J 8.7 Hz,
ArH), 7.34-7.29 (1H, t, J 7.6 Hz, ArH), 7.00 (1H, d, J 8.7 Hz, ArH), 5.07, 4.68 (2H, 2s, NCH2CO), 4.19-4.12 (2H, m,
NCH2CH3), 3.79 (3H, s, OCH3), 1.25-1.20 (3H, t, J 7.0 Hz, NCH2CH3). 13C NMR (75 MHz, DMSO-d6): δ 167.6, 160.6
149.7 (3CO), 146.7 (Ar-C), 143.8 (CH), 139.2, 135.5, 128.3, 126.5, 122.7, 114.8, 114.2 (Ar-C), 55.2 (OCH3), 42.3
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(NCH2CO), 38.2 (NCH2CH3), 12.3 (CH3). Anal. Calcd. For C20H20N4O4 (380.40): C, 63.15; H, 5.30; N, 14.73; Found
C, 62.91; H, 5.26; N, 14.95.
1-Ethyl-2,4-dioxo-(1H,3H)-quinazolin-3-ylacetyl 3\-nitrobenzylidene hydrazone (8c). Yellowish white crystals
(0.37 g, 82%), Rf = 0.64(S1), mp 280-283 oC. 1H NMR (300 MHz, DMSO-d6): δ 11.91 (1H, s, NH), 8.47 (1H, s, ArH),
8.22 (1H, d, J 8.1 Hz, ArH), 8.33, 8.13 (1H, 2s, CH), 8.06 (1H, d, J 7.5 Hz, ArH), 7.82-7.76 (1H, t, J 7.6 Hz, ArH),
7.72-7.67 (1H, t, J 7.6 Hz, ArH), 7.53 (1H, d, J 8.1 Hz, ArH), 7.33-7.28 (1H, t, J 7.4 Hz, ArH), 5.12, 4.73 (2H, 2s,
NCH2CO), 4.19-4.12 (2H, m, NCH2CH3), 1.24-1.20 (3H, t, J 6.6 Hz, NCH2CH3). 13C NMR (75 MHz, DMSO-d6): δ
168.2, 160.8 149.6 (3CO), 148.1, 144.5 (Ar-C), 141.7 (CH), 139.2, 135.5, 132.8, 130.2, 128.0, 124.0, 122.7, 120.9
114.6, 114.3 (Ar-C), 42.3 (NCH2CO), 38.2 (NCH2CH3), 12.3 (CH3). Anal. Calcd. For C19H17N5O5 (395.37): C, 57.72;
H, 4.33; N, 17.71; Found C, 57.50; H, 4.29; N, 17.96.
1-Ethyl-2,4-dioxo-(1H,3H)-quinazolin-3-ylacetyl 3\-methoxy-4\-hydroxybenzylidene hydrazone (8d). White
crystals (0.42 g, 94%), Rf = 0.51(S1), mp 275-277 oC. 1H NMR (300 MHz, DMSO-d6): δ 11.48 (1H, s, NH), 9.48 (1H,
s, OH), 8.08 (1H, d, J 7.8 Hz, ArH), 8.10, 7.92 (1H, 2s, CH), 7.81-7.76 (1H, t, J 7.8 Hz, ArH), 7.52 (1H, d, J 8.4 Hz,
ArH), 7.33-7.27 (2H, m, ArH), 7.10-7.06 (1H, t, J 7.5 Hz, ArH), 6.84 (1H, d, J 7.8 Hz, ArH), 5.09, 4.68 (2H, 2s,
NCH2CO), 4.18-4.11 (2H, m, NCH2CH3), 3.83 (3H, s, OCH3), 1.24-1.19 (3H, t, J 6.9 Hz, NCH2CH3). 13C NMR (75
MHz, DMSO-d6): δ 167.6, 160.9 149.7 (3CO), 148.9, 147.4 (Ar-C), 144.4 (CH), 139.2, 135.5, 128.1, 125.4, 122.7,
121.9, 121.3, 115.4, 114.3, 109.3 (Ar-C), 55.5 (OCH3), 42.5 (NCH2CO), 38.2 (NCH2CH3), 12.3 (CH3). Anal. Calcd.
For C20H20N4O5 (396.4): C, 60.60; H, 5.09; N, 14.13; Found C, 60.41; H, 5.07; N, 14.36.
1-Ethyl-2,4-dioxo-(1H,3H)-quinazolin-3-ylacetyl glycine hydrazide (9). To a solution of 6a (2.0 g, 6.25 mmol) in
methanol (30 ml), hydrazine hydrate (3 ml, 48.0 mmol) was added. The reaction mixture was refluxed for 8
hrs, after cooling to room temperature the precipitated hydrazide was filtered off, washed with water, and
ethanol followed by recrystallization from aqueous ethanol to give white crystals (1.44 g, 72%), Rf = 0.31(S2),
o
1
mp 228-231 C. H NMR (300 MHz, DMSO-d6): δ 8.95 (1H, s, NH), 8.44-8.40 (1H, m, NH), 8.07 (1H, d, J 7.8 Hz,
ArH), 7.83-7.78 (1H, t, J 7.8 Hz, ArH), 7.55 (1H, d, J 7.8 Hz, ArH), 7.34-7.29 (1H, t, J 7.8 Hz, ArH), 4.62 (2H, s,
NCH2CO), 4.25-4.14 (2H, brs, NH2), 4.18-4.11 (2H, m, NCH2CH3), 3.70 (2H, d, J 6.0 Hz, NCH2), 1.27-1.19 (3H, t, J
6.9 Hz, NCH2CH3). 13C NMR (75 MHz, DMSO-d6): δ 167.9, 166.9, 160.9, 149.8 (4CO), 139.3, 135.5, 128.0, 122.6,
114.9, 114.3 (Ar-C), 43.4 (NCH2), 40.3 (NCH2CO), 33.2 (NCH2CH3), 12.3 (CH3). Anal. Calcd. For C14H17N5O4
(319.32): C, 52.66; H, 5.37; N, 21.93; Found C, 52.41; H, 5.33; N, 21.87.
General procedure for the synthesis of hydrazones (10a-d). A mixture of 9 (0.3 g, 0.9 mmol) and carbonyl
compound (1.0 mmol) was refluxed in ethanol (20 ml) for 5 hours. After cooling to room temperature, the
resulting solid was filtered, washed with cold ethanol and recrystallized from aqueous ethanol.
1-Ethyl-2,4-dioxo-(1H,3H)-quinazolin-3-ylacetyl glycyl benzylidene hydrazone (10a). White crystals (0.31 g,
o
1
79%), Rf = 0.62(S2) mp 264-266 C. H NMR (300 MHz, DMSO-d6): δ 11.46, 11.30 (1H, 2s, NH), 8.60-8.57, 8.42-
8.38 (1H, 2m, NH), 8.08 (1H, d, J 7.5 Hz, ArH), 8.22, 7.98 (1H, 2s, CH), 7.82-7.77 (1H, t, J 7.5 Hz, ArH), 7.69-7.29
(6H, m, ArH), 4.66 (2H, s, NCH2CO), 4.30-4.28, 3.86-3.80 (2H, 2m, NCH2), 4.19-4.12 (2H, m, NCH2CH3), 1.24-1.19
(3H, t, J 7.1 Hz, NCH2CH3). 13C NMR (75 MHz, DMSO-d6): δ 170.0, 167.1, 160.9 149.7 (4CO), 146.7 (CH), 143.4,
139.3, 135.5, 134.0, 129.7, 128.7, 128.1, 126.7, 122.6, 114.8, 114.3 (Ar-C), 43.4 (NCH2CO), 38.2 (NCH2CH3),
12.3 (CH3). Anal. Calcd. For C21H21N5O4 (407.42): C, 61.91; H, 5.20; N, 17.19; Found C, 62.00; H, 5.46; N, 17.47.
1-Ethyl-2,4-dioxo-(1H,3H)-quinazolin-3-ylacetyl glycyl 4\-methoxybenzylidene hydrazone (10b). White
o
1
crystals (0.33 g, 82%), Rf = 0.77(S2) mp 248-250 C. H NMR (300 MHz, DMSO-d6): δ 11.33, 11.15 (1H, 2s, NH),
8.58, 8.38 (1H, 2m, NH), 8.08 (1H, d, J 8.1 Hz, ArH), 8.15, 7.92 (1H, 2s, CH), 7.83 (1H, t, J 7.5 Hz, ArH), 7.65-7.52
(3H, m, ArH), 7.34 (1H, t, J 7.5 Hz, ArH), 7.02-6.95 (2H, m, ArH), 4.65 (2H, s, NCH2CO), 4.27-4.20, 4.84-3.80 (2H,
2m, NCH2), 4.19-4.12 (2H, m, NCH2CH3), 3.78 (3H, s, OCH3), 1.24-1.20 (3H, t, J 6.7 Hz, NCH2CH3). 13C NMR (75
MHz, DMSO-d6): δ 170.3, 167.3, 161.3 (3CO), 161.1 (Ar-C), 150.2 (CO), 143.8 (CH), 139.8, 136.0, 129.11, 128.8,
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128.6, 127.1, 123.2, 115.4, 114.7 (Ar-C), 55.7 (OCH3), 43.0 (NCH2CO), 38.7 (NCH2CH3), 12.8 (CH3). Anal. Calcd.
For C22H23N5O5 (437.45): C, 60.40; H, 5.30; N, 16.01; Found C, 60.03; H, 5.53; N, 16.09.
1-Ethyl-2,4-dioxo-(1H,3H)-quinazolin-3-ylacetyl glycyl 3\-nitrobenzylidene hydrazone (10c). Yellowish white
crystals (0.27 g, 64%), Rf = 0.66 (S2), mp 301-304 oC. 1H NMR (300 MHz, DMSO-d6): δ 11.68, 11.60 (1H, 2s, NH),
8.62, 8.49 (1H, 2brs., NH), 8.49-7.27 (7H, m, ArH), 8.42, 8.08 (1H, 2s, CH), 4.66 (2H, s, NCH2CO), 4.35-4.30,
3.90-3.85 (2H, 2m, NCH2), 4.15-4.12 (2H, m, NCH2CH3), 1.23-1.19 (3H, t, J 6.3 Hz, NCH2CH3). 13C NMR (75 MHz,
DMSO-d6): δ 170.3, 166.9, 160.8, 149.7 (4CO), 148.1, 144.3 (Ar-C), 141.1 (CH), 139.3, 135.8, 133.1, 130.2 128.0,
124.1, 122.6, 120.8, 114.8, 114.3 (Ar-C), 43.2 (NCH2CO), 38.2 (NCH2CH3), 12.3 (CH3). Anal. Calcd. For
C21H20N6O6 (452.42): C, 55.75; H, 4.46; N, 18.58; Found C, 55.52; H, 4.44; N, 18.71.
1-Ethyl-2,4-dioxo-(1H,3H)-quinazolin-3-ylacetyl glycyl 3\-methoxy-4\-hydroxybenzylidene hydrazone (10d).
o
1
White crystals (0.18 g, 63%), Rf = 0.42 (S2), mp 258-261 C. H NMR (300 MHz, DMSO-d6): δ 11.28, 11.09 (1H,
2s, NH), 9.45 (1H, s, OH), 8.63-8.58, 8.41-8.37 (1H, 2m, NH), 8.07 (1H, d, J 7.5 Hz, ArH), 8.10, 7.86 (1H, 2s, CH),
7.80-7.75 (1H, t, J 7.8 Hz, ArH), 7.51 (1H, d, J 8.4 Hz, ArH), 7.32-7.22 (2H, m, ArH), 7.08-7.02 (1H, t, J 8.4 Hz,
ArH), 6.84-6.78 (1H, t, J 8.5 Hz, ArH), 4.66 (2H, s, NCH2CO), 4.30-4.25, 3.85-3.81 (2H, 2m, NCH2), 4.20-4.10 (2H,
m, NCH2CH3), 3.81(3H, s, OCH3), 1.23-1.18 (3H, t, J 6.9 Hz, NCH2CH3). 13C NMR (75 MHz, DMSO-d6): δ 169.6,
166.8, 164.7, 1.60.8 (4CO), 149.7, 148.6 (Ar-C), 143.8 (CH), 139.2, 135.4, 128.0, 125.4, 122.6, 121.2, 115.4,
114.8, 114.2, 109.1 (Ar-C), 55.4 (OCH3), 43.4 (NCH2CO), 38.2 (NCH2CH3), 12.3 (CH3). Anal. Calcd. For C22H23N5O6
(453.45): C, 58.27; H, 5.11; N, 15.44; Found C, 58.04; H, 5.20; N, 15.68.
1-Phthalylglycyl-1,3-dicyclohexylurea (11). To a cold solution of 2 (1.17 g, 5.0 mmol) and phthalylglycine
o
(1.03g, 5.0 mmol) and HOBt (0.68g, 5.0 mmol) in methylene chloride (20.0 ml) at 0 C, DCC (1.15 g, 5.5 mmol)
o
was added. The reaction mixture was stirred at 0 C for 5 min and at room temperature for 3 hrs. The formed
precipitate was filtered off and the filtrate was evaporated under reduced pressure. The residue was dissolved
in ethyl acetate and washed twice with saturated of NaCl solution, 5% NaHCO3 solution and water. After
drying over anhydrous sodium sulphate, the solvent was evaporated and the remaining residue was
crystallized from ethyl acetate-petroleum ether to yield white crystals of 1-phthalylglycyl-1,3-dicyclohexylurea
o
1
11 (1.59 g, 79%), Rf = 0.12(S3) mp 172-175 C. H NMR (300 MHz, DMSO-d6): δ 8.06-7.80 (4H, m, ArH), 5.65-
5.45 (1H, m, NH), 4.31 (1H, s, NCH2), 3.40-3.25 (2H, m, 2NCH), 1.75-1.00 (20H, m, 10 CH2 cyclohexyl rings).
Anal. Calcd. For C23H29N3O4 (411.49): C, 67.13; H, 7.10; N, 10.21; Found C, 67.30; H, 7.39; N, 10.36.
o
Phthalylglycine 2-(1-ethyl-2,4-dioxo-(1H,3H)-quinazolin-3-yl)ethyl ester (12). To a cold solution (0 C) of 2
(1.17 g, 5 mmol), phthalylglycine (1.03g, 5 mmol) and catalytic amount of DMAP (0.02 g, 0.16 mmol) in
o
methylene chloride (20.0 ml) DCC (1.15 g, 5.5 mmol) was added. The reaction mixture was stirred at 0 C for 5
min and at room temperature for 3 hrs. The precipitated dicyclohexylurea (DCU) was filtered off and the
filtrate was evaporated under reduced pressure. The residue dissolved in methylene chloride and, if necessary,
filtered from of any further residual DCU. The solution was washed twice with 0.5M HCl, saturated solution of
NaHCO3 and water. After drying over anhydrous Na2SO4, the solvent was evaporated and the remaining
residue was crystallized from ethyl acetate-petroleum ether to yield white crystals of 12 (1.35 g, 64%), Rf =
0.65(S3) mp 156-159 oC. 1H NMR (300 MHz, CDCl3): δ 8.18 (1H, d, J 7.8 Hz, ArH), 7.88- 7.64 (5H, m, ArH), 7.26-
7.19 (2H, m, ArH), 4.49-4.38 (4H, m, NCH2CH2O), 4.41 (1H, s, NCH2), 4.23-4.16 (2H, m, NCH2CH3), 1.37-1.32 (3H,
m, NCH2CH3). 13C NMR (75 MHz, CDCl3): δ 167.2, 161.7, 150.4 (CO), 139.6, 135.1, 134.0, 132.0, 129.2, 123.5,
122.7, 115.5, 113.4 (Ar-C), 62.9 (NCH2CH2O), 40.1 (NCH2CH2O), 38.8 (NCH2CH3), 12.5 (CH3). Anal. Calcd. For
C22H19N3O6 (421.40): C, 62.70; H, 4.54; N, 9.97; Found C, 63.03; H, 4.85; N, 10.13.
2-(1-Ethyl-2,4-dioxo-(1H,3H)-quinazolin-3-yl)ethyl acetate (13a)
Method A. To a cold solution (0 oC) of 2 (1.17 g, 5 mmol), acetic acid (0.3 mL, 5.2 mmol) and catalytic amount
of DMAP (0.02 g, 0.16 mmol) in methylene chloride (20.0 ml) DCC (1.15 g, 5.5 mmol) was added. Afterward,
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the reaction mixture was treated as described above under the synthesis of the phthalylglycine ester
derivative 12 to yield white crystals of 13a (0.85 g, 61%), Rf = 0.64(S3) mp 76-79 oC.
Method B. A mixture of 2 (1.17 g, 5 mmol), acetic anhydride (2.0 ml) in pyridine (5.0 ml) was stirred at 0 oC for
1 hr. and at room temperature overnight. The reaction mixture was poured into ice, and the solid precipitate
was filtered, washed with water and dried in air. Crystallization from ethyl acetate / petroleum ether yielded
white crystals of 13a (1.06 g, 76%), Rf = 0.64(S3) mp 78-80 oC. 1H NMR (300 MHz, CDCl3): δ 8.18 (1H, d, J 7.8 Hz,
ArH), 7.66-7.61 (1H, m, ArH), 7.22- 7.17 (2H, m, ArH), 4.41-4.35 (4H, m, NCH2CH2O), 4.16-4.11 (2H, m,
NCH2CH3), 1.96 (3H, s, CH3CO), 1.33-1.28 (3H, m, NCH2CH3). 13C NMR (75 MHz, CDCl3): δ 170.7, 161.6, 150.3
(3CO), 139.4, 135.0, 129.0, 122.6, 115.4, 113.2 (Ar-C), 61.2 (OCH2), 40.2 (NCH2), 38.6 (NCH2CH3), 20.6 (CH3),
12.3 (CH3). Anal. Calcd. For C14H16N2O4 (276.29): C, 60.86; H, 5.84; N, 10.14; Found C, 60.51; H, 5.80; N, 9.89.
2-(1-Ethyl-2,4-dioxo-(1H,3H)-quinazolin-3-yl)ethyl benzoate (13b)
o
Method A: To a cold solution (0 C) of 2 (1.17 g, 5.0 mmol), benzoic acid (0.6 g, 5.0 mmol) and catalytic
amount of DMAP (0.02 g, 0.16 mmol) in methylene chloride (20.0 ml) DCC (1.15 g, 5.5 mmol) was added.
Afterward, the reaction mixture was treated as described above under the synthesis of the phthalylglycine
ester derivative 12 to yield white crystals of 12b (1.1.16 g, 69%), Rf = 0.74(S3) mp 129-131 oC.
Method B. To a cold solution of 2 (1.17 g, 5 mmol), in pyridine (5.0 ml) benzoyl chloride (0.6 ml, 5 mmol) was
added. The reaction mixture worked up as indicated in the synthesis of 13a (Method B). Crystallization from
o
1
ethyl acetate / petroleum ether afforded white crystals of 13b (1.35 g, 80%), Rf = 0.74(S3) mp 130-133 C. H
NMR (300 MHz, CDCl3): δ 8.24 (1H, d, J 7.8 Hz, ArH), 8.01 (2H, d, J 7.8 Hz, ArH), 7.67- 7.19 (6H, m, ArH), 4.63-
4.54 (4H, m, NCH2CH2O), 4.21-4.14 (2H, m, NCH2CH3), 1.33-1.28 (3H, m, NCH2CH3). 13C NMR (75 MHz, CDCl3): δ
166.4, 161.7, 150.4 (3CO), 139.6, 135.1, 132.8, 130.0, 129.6, 129.2, 128.2, 122.7, 115.6, 113.4 (Ar-C), 62.1
(OCH2), 40.3 (NCH2), 38.8 (NCH2CH3), 12.4 (CH3). Anal. Calcd. For C19H18N2O4 (338.36): C, 67.44; H, 5.36; N,
8.28; Found C, 67.16; H, 5.30; N, 8.36.
General method for the synthesis of Boc-amino acid 2-(1-ethyl-2,4-dioxo-(1H,3H)-quinazolin-3-yl)ethyl
esters (14a-c). To a cold solution (0 oC) of 2 (1.17 g, 5 mmol), Boc-amino acid (5 mmol) and catalytic amount of
DMAP (0.02 g, 0.16 mmol) in dry methylene chloride (20.0 ml) dicyclohexylcarbodiimide (1.15 g, 5.5 mmol)
o
was added. The reaction mixture was stirred at 0 C for 5 min and at room temperature for 3 hrs. The
precipitated DCU was filtered off and the filtrate was evaporated under reduced pressure. The residue was
dissolved in methylene chloride and, if necessary, filtered from any further remaining DCU, washed twice with
0.5M HCl, saturated NaHCO3 solution and water. After drying over anhydrous sodium sulphate, the solvent
was evaporated and the remaining residue was precipitated from ethyl acetate by petroleum ether to yield
14a-c.
Boc-glycine 2-(1-ethyl-2,4-dioxo-(1H,3H)-quinazolin-3-yl)ethyl ester (14a). Yellow oil (1.28 g, 65%), Rf =
1
0.49(S4). H NMR (300 MHz, CDCl3): δ 8.08 (1H, d, J 8.1 Hz, ArH), 7.59- 7.54 (1H, m, ArH), 7.13-7.09 (2H, m,
ArH), 5.24-5.19 (1H, brs, NH-Boc), 4.35-4.30 (2H, m, NCH2CH2O), 4.27-4.23 (2H, m, NCH2CH2O), 4.10-4.03 (2H,
m, NCH2CH3), 3.76-3.74 (2H, m, NCH2CO), 1.29 (9H, s, 3CH3), 1.25-1.14 (3H, m, NCH2CH3). 13C NMR (75 MHz,
CDCl3): δ 169.9, 161.4, 155.4, 150.1 (4CO), 139.2, 134.9, 128.7, 122.4, 115.1, 113.1 (Ar-C), 79.2 (O-C, t-butyl),
61.9 (NCH2CH2O), 42.1 (NCH2CO), 39.9 (NCH2CH2O), 38.5 (NCH2CH3), 27.9 (3CH3, t-butyl), 12.2 (CH3). Anal.
Calcd. For C19H25N3O6 (391.42): C, 58.30; H, 6.44; N, 10.74; Found C, 58.11; H, 6.24; N, 10.97.
Boc-L-leucine 2-(1-ethyl-2,4-dioxo-(1H,3H)-quinazolin-3-yl)ethyl ester (14b). Yellow oil (1.51 g, 67%), Rf =
1
0.74(S4). H NMR (300 MHz, CDCl3): δ 8.07 (1H, d, J 7.8 Hz, ArH), 7.58- 7.53 (1H, m, ArH), 7.12-7.07 (2H, m,
ArH), 5.07-5.01 (1H, brs, NH-Boc), 4.34-4.20 (4H, m, NCH2CH2O), 4.18-4.03 (3H, m, NCH, NCH2CH3), 1.59-1.33
(3H, m, CH2, CH), 1.26 (9H, s, 3CH3), 1.24-1.14 (3H, m, NCH2CH3), 0.80 (6H, d, J 6.3 Hz, 2CH3). 13C NMR (75 MHz,
CDCl3): δ 172.6, 161.3, 155.0, 149.9 (4CO), 139.2, 134.8, 128.7, 122.3, 115.1, 113.1 (Ar-C), 78.9 (O-C, t-butyl),
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61.7 (NCH2CH2O), 51.4 (NCH), 41.0 (NCH2CH2O), 39.8 (NCH2CH3), 38.4 (CH2), 27.8 (3CH3, t-butyl), 24.2 (CH),
22.5 (CH3), 21.5 (CH3), 12.1 (CH3). Anal. Calcd. For C23H33N3O6 (447.52): C, 61.73; H, 7.43; N, 9.39; Found C,
61.51; H, 7.35; N, 9.62.
Boc-L-tryptophane 2-(1-ethyl-2,4-dioxo-(1H,3H)-quinazolin-3-yl)ethyl ester (14c). White crystals (1.68 g,
o
63%), Rf = 0.41(S4) mp 138-141 C. 1H NMR (300 MHz, CDCl3): δ 8.25 (1H, d, J 7.8 Hz, ArH), 7.96 (1H, brs, Ind-
NH), 7.71- 7.66 (1H, t, J 7.8 Hz, ArH), 7.56 (1H, d, J 7.8 Hz, ArH), 7.27-7.04 (5H, m, ArH), 6.99 (1H, s, Ind-2-H),
5.20-5.13 (1H, brs, NH-Boc), 4.62 (1H, m, NCH), 4.40-4.34 (4H, m, NCH2CH2O), 4.16-4.10 (2H, m, NCH2CH3),
13
3.09-3.05 (2H, m, CH2), 1.39 (9H, s, 3CH3), 1.35-1.26 (3H, m, NCH2CH3). C NMR (75 MHz, CDCl3): δ 171.8,
161.7, 155.1, 150.4 (4CO), 139.5, 135.1, 129.1, 122.8, 121.8, 119.3, 118.6, 115.5, 113.4, 111.0 (Ar-C), 79.5 (O-C,
t-butyl), 62.3 (NCH2CH2O), 54.3 (NCH), 40.1 (NCH2CH2O), 38.8 (NCH2CH3), 28.2 (3CH3, t-butyl), 12.4 (CH3). Anal.
Calcd. For C28H32N4O6 (520.58): C, 64.60; H, 6.20; N, 10.76; Found C, 64.48; H, 6.24; N, 10.91.
General method for the synthesis of amino acid 2-(1-ethyl-2,4-dioxo-(1H,3H)-quinazolin-3-yl)ethyl ester
hydrochloridse (15a-c). Boc-amino acid ester derivative 14a-c (1.5 mmol) was stirred in 1M HCl in ethyl
acetate (15 mL) for 2 hrs. at room temperature. Afterward, the reaction mixture was concentrated and left to
cool. The formed precipitate was filtered off, washed with dry ethyl acetate and dried.
Glycine 2-(1-ethyl-2,4-dioxo-(1H,3H)-quinazolin-3-yl)ethyl ester hydrochloride (15a). White crystals (0.32 g,
+
63%), Rf = 0.40 (S2), mp 184-186 oC. 1H NMR (300 MHz, DMSO-d6): δ 8.90-8.50 (3H, brs, NH3 ), 8.03 (1H, d, J 7.8
Hz, ArH), 7.78- 7.72 (1H, t, J 7.9 Hz, ArH), 7.49 (1H, d, J 8.4 Hz, ArH), 7.29-7.24 (1H, t, J 7.6 Hz, ArH), 4.40-4.36
(2H, m, NCH2CH2O), 4.23-4.20 (2H, m, NCH2CH2O), 4.14-4.07 (2H, m, NCH2CH3), 3.65 (2H, s, NCH2CO), 1.25-1.16
13
(3H, t, J 6.9 Hz, NCH2CH3). C NMR (75 MHz, DMSO-d6): δ 167.4, 161.2, 149.9 (3CO), 139.2, 135.5, 128.0,
122.6, 114.8, 114.3 (Ar-C), 62.2 (OCH2), 38.3 (NCH2CH3), 12.3 (CH3). Anal. Calcd. For C14H18N3O4Cl (327.76): C,
51.30; H, 5.54; N, 12.82; Found C, 51.56; H, 5.62; N, 12.59.
L-Leucine 2-(1-ethyl-2,4-dioxo-(1H,3H)-quinazolin-3-yl)ethyl ester hydrochloride (15b). White crystals (0.25 g,
+
43%), Rf = 0.56 (S2), mp 177-180 oC.1H NMR (300 MHz, CDCl3): δ 8.90-8.70 (3H, brs, NH3 ), 8.16 (1H, d, J 7.8 Hz,
ArH), 7.66- 7.60 (1H, t, J 7.9 Hz, ArH), 7.27-7.16 (2H, m, ArH), 4.52-4.35 (4H, m, NCH2CH2O), 4.18-4.09 (2H, m,
NCH2CH3), 4.01-3.97 (1H, m, NCHCO), 1.91-1.72 (3H, m, CH2, CH), 1.32-1.27 (3H, t, J 7.0 Hz, NCH2CH3), 0.86
(6H, d, J 5.7 Hz, 2CH3). 13C NMR (75 MHz, CDCl3): δ 169.4, 161.6, 150.2 (3CO), 139.4, 135.1, 129.1, 122.7, 115.3,
113.4 (Ar-C), 63.2 (NCH2CH2O), 51.6 (NCH), 39.9 (NCH2CH2O), 39.0 (NCH2CH3), 38.8 (CH2), 24.2 (CH), 22.1 (CH3),
21.7 (CH3), 12.4 (CH3). Anal. Calcd. For C18H26N3O4Cl (383.87): C, 56.32; H, 6.83; N, 10.95; Found C, 56.47; H,
6.90; N, 10.74.
L-Tryptophane 2-(1-ethyl-2,4-dioxo-(1H,3H)-quinazolin-3-yl)ethyl ester hydrochloride (15c). White crystals
(0.52 g, 74%), Rf = 0.47 (S2), mp (dec) 146-149 oC. 1H NMR (300 MHz, CDCl3): δ 9.68 (1H, brs, Ind-NH), 8.50-8.20
+
(3H, brs, NH3 ), 8.04 (1H, d, J 7.8 Hz, ArH), 7.55-6.75 (8H, m, 7 ArH, Ind-2-H), 4.17-3.90 (7H, m, NCH,
13
NCH2CH2O, NCH2CH3), 3.50-3.20 (2H, m, CH2), 1.25-1.18 (3H, m, NCH2CH3). C NMR (75 MHz, CDCl3): δ 169.0,
161.7, 150.1 (3CO), 139.2, 136.1, 135.2, 128.9, 126.5, 126.1, 122.9, 121.3, 118.8, 117.6, 115.1, 113.4, 111.7,
105.7 (Ar-C), 63.5 (NCH2CH2O), 53.4 (NCH), 39.8 (NCH2CH2O), 38.8 (NCH2CH3), 25.7 (CH2), 12.4 (CH3). Anal.
Calcd. For C23H25N4O4Cl (456.92): C, 60.46; H, 5.51; N, 12.26; Found C, 60.68; H, 5.63; N, 12.03.
In vitro antiproliferative activity. First, a preliminary investigation of antitumor activity of the synthesized
compounds were performed at 100 g/mL. Based upon these study the inactive compounds were excluded
from further investigation. Cytotoxicity of the newly synthesized compounds was tested against human liver
carcinoma cell line (HepG2) using the method of Skehan et al.32
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Supplementary Material
Synthesis of the starting compounds 1 and 2 and copies of 1H and 13C NMR spectra of the new compounds can
be found in the supplementary material file.
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