Synthesis of new 1,2,3-triazol-4-yl-quinazoline nucleoside and acyclonucleoside analogues

Article abstract of DOI:10.3390/molecules19033638

In this study, we describe the synthesis of 1,4-disustituted-1,2,3- triazoloquinazoline ribonucleosides or acyclonucleosides by means of 1,3-dipolar cycloaddition between various O or N-Alkylated propargyl-quinazoline and 1'-Azido-2',3',5'-tri-Obenzoylribose or activated alkylating agents under microwave conditions. None of the compounds selected showed significant anti-HCV activity in vitro.

Full text of DOI:10.3390/molecules19033638

Molecules 2014, 19, 3638-3653; doi:10.3390/molecules19033638
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis of New 1,2,3-Triazol-4-yl-quinazoline Nucleoside and
Acyclonucleoside Analogues
Abdelaaziz Ouahrouch 1,2, Moha Taourirte 1,*, Joachim W. Engels 3,*, Soumaya Benjelloun 4 and
Hassan B. Lazrek 2,*
1
Laboratory of Bioorganic and Macromolecular Chemistry, Department of Chemistry, Faculty of
Sciences and Technology Gueliz (FSTG), BP 549, Marrakech 40000, Morocco
2
Laboratory of Biomolecular and Medicinal Chemistry, Department of Chemistry, Faculty of
Sciences Semlalia, Marrakech 40000, Morocco
3
Institute for Organic Chemistry and Chemical Biology, Goethe-University Frankfurt am Main,
Max-von-Laue-Strasse 7, D-60438 Frankfurt am Main, Germany
4
Viral Hepatitis Laboratory Pasteur Institute Morocco, 1, Place Louis Pasteur, 20360,
Casablanca 20001, Morocco
* Authors to whom correspondence should be addressed; E-Mails: taourirte@gmail.com (M.T.);
joachim.engels@chemie.uni-frankfurt.de (J.W.E.); hblazrek50@gmail.com (H.B.L.);
Tel.: +212-5-2443-4688 (M.T.); Fax: +212-5-2443-3170 (M.T.); Tel.: +49-69-7982-9150 (J.W.E.);
Fax: +49-69-7982-9148 (J.W.E.).
Received: 13 January 2014; in revised form: 6 March 2014 / Accepted: 17 March 2014 /
Published: 24 March 2014
Abstract: In this study, we describe the synthesis of 1,4-disustituted-1,2,3-triazolo-
quinazoline ribonucleosides or acyclonucleosides by means of 1,3-dipolar cycloaddition
between various O or N-alkylated propargyl-quinazoline and 1'-azido-2',3',5'-tri-O-
benzoylribose or activated alkylating agents under microwave conditions. None of the
compounds selected showed significant anti-HCV activity in vitro.
Keywords: quinazoline ribonucleosides; 1,2,3-triazole-acyclonucleosides; Huisgen
cycloaddition; quinazolinone alkylation; HCV

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1. Introduction
An estimated 150 million people worldwide are chronically infected with hepatitis C virus (HCV)
and have an increased risk of eventually developing liver cirrhosis or liver cancer [1]. We believe that
a successful approach to cure HCV in most patients will likely require treatment with a combination of
drugs that attacks different mechanisms necessary for replication and survival of HCV. Currently,
patients undergo treatment with a combination of pegylated interferon alpha and ribavirin or a virus-
specific protease inhibitor like telaprevir or boceprevir [2–4].
Heterocyclic structures are the basic elements of many pharmaceuticals, agrochemicals and
veterinary products. Quinazolinone derivatives are an important class of these heterocyclic compounds
that has been shown to display a broad-range of biological activities, for example, anticancer, diuretic,
anti-inflammatory, anti-convulsant and antihypertensive activities [5–7].
In addition, 1,2,3-triazole nucleosides and carbanucleosides are N-Heterocyclic compounds which
have been the subject of considerable research, mainly due to their value in synthetic organic
chemistry [8–14] based on the Sharpless-Meldal modified Huisgen reaction. The classical 1,3-dipolar
cycloaddition of azides and alkynes discovered by Huisgen [15] often gives mixtures of regioisomers
(1,4- and 1,5-disubstituted triazoles). “Click Chemistry” is a term that was developed by Sharpless and
independently by Meldal to illustrate a regioselective 1,3-dipolar cycloaddition using Cu(I) salts as
catalyst. The catalyst can be added directly in the form of Cu(I) or Cu(II) salts using reducing agents to
form active Cu(I) in-situ [16,17]. Cu(I) salts require at least an amine base to form the Cu-acetylide
complexes. Many studies have shown that the presence of base under the process conditions provides
stability for Cu(I) salts against oxidation. It has been used especially in anhydrous media and also
under catalytic conditions [18].
In addition, the combination of two different and independently linked hybrid compounds can
display synergy and result in a pharmacological potency greater than the sum of each individual
moiety’s potencies. For instance, nucleoside analogues incorporating triazole units are a valuable area
of therapeutic research, and some triazole-containing compounds have shown activities against
hepatitis and HIV-1 [19,20].
We previously reported the preparation of various 1,2,3-triazole acyclonucleosides from
propargylated nucleobases by high temperature and long duration copper-free Huisgen 1,3-dipolar
cycloadditiona and the evaluation of the resulting compounds for their HIV activity [21]. Recently, we
also reported the preparation of several triazolo-acyclic nucleoside phosphonates using copper(I)-
catalyzed Huisgen 1,3-dipolar cycloadditions between azido alkylphosphonates and propargylated
nucleobases and the evaluation of the resulting compounds for their HIV and HCV activity [22–27].
The poor treatment response, combined with often-severe side effects induced by therapy,
highlights the need for improved antiviral drugs with better efficacy and safety profiles. Furthermore,
in continuation of our research program centered on click chemistry [28,29], the aim of the present
work was to synthesize some new hybrid compounds combining the two heterocycles: quinazolinone
and 1,2,3-triazole. The new compounds were also assessed for their anti-HCV activities.

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2. Results and Discussion
2.1. Synthesis of Protected Nucleosides and Acyclonucleosides 6a–i
Typically, quinazolinone structures were constructed using anthranilic acid or its derivatives via a
sequence of acylation and condensation, which requires strong acidic or basic reaction conditions [30–32].
The quinazoline derivatives were prepared from anthranilic acid (1) in three steps. Initially, the acid
was reacted with benzoyl chloride in anhydrous pyridine at 0–5 °C for one hour. Afterwards the
reaction mixture was stirred (two hours) at room temperature until 2-phenylbenzoxazinone (2a) was
formed [33,34]. Alternatively, 2-methylbenzoxazinone (2b) was obtained by reaction of anthranilic
acid with acetic anhydride using microwave irradiation [35,36]. The benzoxazinones were further
treated with formamide under microwave irradiation to obtain the quinazolinones 3a–b. On the other
hand, the synthesis of quinazolin-4-one 3c was achieved by condensing anthranilic acid with
2.5 equivalents of formamide under microwave irradiation [37] (Scheme 1).
Scheme 1. Synthesis of benzoxazinones 2a,b.
O
2.5 eq. , 15 min
H2N-CHO / MWI
( R1= -H )
CO2H
NH2
NH
N
R1
R1=-Ph
3a :
3b :
3c :
1
R1=-Me
R =
-H
1
1.5 eq. / 10 min
(MeCO)2O / MWI
H2N-CHO : 2.5 eq.
MWI , 10 min
Or
O
N
PhCOCl : 1.1 eq.
Pyridine
0 °C, 1h - r.t. 2h
O
R1
2a: R1 = -Ph
2b: R1 = -Me
The alkylation of quinazol-4-ones which are substituted in position 2 sometimes leads to two
isomers resulting from competing N-alkylation and O-alkylation and the ratio of these isomers depends
on the substituent at position 2. An earlier study confirmed that the substituents and the reaction
conditions play a significant role in influencing the ratio of O-alkylation vs. N-alkylation [38]. In this
investigation, the quinazolinones 3a‒c were treated with propargyl bromide in the presence of
potassium t-butoxide. The reaction was carried out using DMF as the solvent [39–41] (Scheme 2). The
alkylation of 2-methylquinazolin-4-ones 2b and 2c leads exclusively to the formation of
N-propargylated quinazolines, and O-propargylated isomers were not detected. In the case of
2-phenylquinazolin-4-one (2a), alkylation preferentially results in O-propargylation, with O and
N-alkylated products 5a and 4a being obtained in a ratio of 58:23.

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Scheme 2. Synthesis of alkylated quinazolines 4a–c and 5a.
O
O
O
1.1 eq. / 2.5 eq.
NH
N
N
t-BuOK / C3H3Br
+
DMF, r.t.
15 min
N
R1
N
R1
N
R1
-Ph
5a : R1=
-Ph
4a : R1=
R1=-Ph
R1=-Me
3a :
3b :
3c :
4b :
R1=
-Me
-H
4c :
R =
1
R =
-H
1
The propargylated quinazolines 4 and 5 were used in the 1,3-dipolar cycloaddition reaction to link
1,2,3-triazole with the quinazoline nucleus to yield compounds 6. Reaction of the triple bonds of
propargylated quinazoline and the azide of sugar and pseudo-sugar was performed under microwave
irradiation using Cul as catalyst without solvent (Scheme 3).
Scheme 3. Syntheses of 1,2,3-triazoles-quinazoline 6a–i and 7a–i.
Reaction conditions: (i) 5a/4b–c (1 mmol), alkylazide (2.5 mmol), Et3N (1.1 mmol), CuI (0.1 eq), MWI
(400W, 2 min); (ii) 6a,d,g (1 mmol), NaOMe (1 eq), MeOH, r.t (30 min) or 6b–c,e,f,h,i (1 mmol), K2CO3
(1 eq), MeOH, r.t (15 min).
This protocol (click chemistry) for the formation of the triazole rings is efficient, easy and
convenient and typically gives almost quantitative reaction yields [42]. The cycloaddition reaction is
drawn in Scheme 3 and the obtained products are tabulated in Table 1.

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Table 1. Synthesized 1,2,3-triazoloquinazolines 6a–i and 7a–i.
Product
6a
Yielda (%)
Product
7a
Yield a (%)
95
88
93
93
87
86
84
90
89
98
86
88
97
95
90
98
93
94
6b
7b
6c
7c
6d
7d
6e
7e
6f
7f
6g
7g
6h
7h
6i
7i
a Yields of isolated products.
1
13
We characterized the structures of all products by H-NMR, C-NMR and mass spectrometry. In
addition, the structures of 6g and 6i were confirmed by X-ray crystallographic analysis. The structure
of crystal (a) illustrates that the anomeric configuration at the C1'-stereocentre has not been affected
during the click reaction, the steric effect of benzoyl group in the position 2' and 3' (ribose) directs the
reaction towards the β-configuration. The crystal structures of these compounds are shown in
Figure 1 [43,44].
Figure 1. X-ray crystal structures of compounds (a) 6g and (b) 6i with the atom numbering
used in the crystallographic analysis.
2.2. Deprotection of Nucleosides and Acyclonucleosides: Preparation of 7a–i
For deprotection base catalyzed methods were employed. Sodium methoxide (NaOMe) in methanol
was used for the deprotection of the benzoyl group of compounds 6a,d,g [45]. On the other hand, the
deprotection of the acetyl group of compounds 6b,c,e,f,h,i was carried out using potassium carbonate
(K2CO3) in methanol (Scheme 3 and Table 1). The structure of 7c was confirmed by X-ray
crystallographic analysis. The crystal structure of this compound is shown in Figure 2 [46].

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Figure 2. X-ray molecular structure of compound 7c.
Finally, we were also interested in studying the biological activity of 1,2,3-triazole ribonucleosides
7a‒i. These derivatives were tested in vitro to evaluate their anti- HCV activity. None of the new
compounds were found to inhibit HCV replication in vitro (Table 2).
Table 2. Anti-HCV activity of compounds 7a–i.
Compound
CC50 (µM) a
IC50 (µM) b
SI c
7a
≥50 µM
≥100 µM
≥50 µM
≥100 µM
≥50 µM
≥50 µM
≥100 µM
≥50 µM
≥50 µM
>300
>10
>10
>10
>10
>10
>10
>10
>10
>10
1.5
5
10
5
7b
7c
7d
10
5
7e
7f
5
7g
10
5
7h
7i
5
2CmeCyt
aIFNB2
200
6667
>10,000 d
1.5 d
a
b
CC50 Concentrations of compound required for 50% extinction of Huh 5.2 cells; IC50 Concentrations of
c
d
compound achieving 50% inhibition of the replicon system; SI selectivity index = CC50/IC50; interferon
reported as IU/mL.
Antiviral activity was assessed in a 3-day cell culture assay using the HCV-replicon-containing cell
line, AVA5 (genotype 1b, CON1) (provided to GUMC by Apath, Inc., Brooklyn, NY, USA) as
previously described [47].
3. Experimental
3.1. General
13
1H- and C-NMR spectra were recorded in CDCl3 or DMSO-d6 on a Bruker 300 MHz instrument
using SiMe4 as internal standard. Chemical shifts are given in ppm and coupling constants (J) in MHz

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(br, broad; m, multiplet; t, triplet; d, doublet; and s, singlet). Mass spectra were obtained using ESI/MS
and MALDI-TOF-MS. Reactions were carried out in a microwave oven Model AVM510/WP/WH.
The reactions were controlled by thin layer chromatography (TLC) on precoated silica gel 60 F254
(Merck, Darmstadt, Germany); UV light was used for visualization of the spots. All products were
purified by column chromatography on silica gel (100–200 mesh) Merck.
3.2. Synthesis of 2-Substituted Quinazolinones
3.2.1. Preparation of 2-Phenylquinazolin-4-one (3a) [36]
Initially, anthranilic acid (1, 2 g, 14.5 mmol) was dissolved in dry pyridine (20 mL). Then benzoyl
chloride (1.1 equiv) was added dropwise at 0 °C. The reaction mixture was maintained at 0 °C for 1 h
and then allowed to stir at room temperature for 2 h, during which time a solid product precipitated
out. The mixture was neutralized using a saturated solution of sodium bicarbonate. The pale yellow
solid was filtered and washed with water. The product, 2-phenylbenzo[d][1,3]-oxazin-4-one (2a) thus
obtained was reacted with formamide under microwave irradiation to obtain 3a. The crude compound
obtained was crystallized in ethanol; Mp 225–226 °C; Yield 83%; Rf 0.5; eluent CH2Cl2/MeOH = 99/1,
v/v; 1H-NMR (CDCl3): δ 7.61 (m, 4H, H-Aromatic), 7.83 (m, 1H, H-Aromatic), 8.01 (m, 1H, H-Aromatic),
8.24 (m, 3H, H-Aromatic), 11.9 (s, 1H, N-H). 13C-NMR (CDCl3): δ 120.81 (C-Aromatic), 126.67,
127.46, 127.85, 128.01, 129.90, 130.11, 131.66, 132.81, 134.93 (CH-Aromatic), 129.04, 149.54, 151.81
(C-Aromatic), 164.04 (CO).
3.2.2. Preparation of 2-Methylquinazolin-4-one (3b) [38]
A mixture of anthranilic acid (1, 500 mg, 3.64 mmol) and acetic anhydride (1.5 eq) was reacted
under microwave irradiation at 400W until total conversion (10 min). After this first step,
2-methylquinazolin-4-one (3b) was obtained by addition of formamide (2.5 equiv) to the reaction
mixture and irradiated by microwave for 10 min. After cooling to room temperature, the solid obtained
was recrystallized from ethanol; Mp 238–240 °C; Yield 94%; Rf 0.65; eluent CH2Cl2/MeOH = 99/1,
v/v; 1H-NMR (CDCl3) δ 2.34 (s, 3H, CH3-Aromatic), 7.34–8.02 (m, 4H, H- Aromatic), 12.12 (br s, 1H,
13
N-H). C-NMR (CDCl3) δ 39.16 (-CH3), 123.31 (C-Aromatic), 125.73, 126.64, 127.15, 134.63 (CH-
Aromatic), 156.02, 154.16 (C-Aromatic), 161.63 (CO).
3.2.3. Preparation of Quinazolin-4-one (3c) [38]
Anthranilic acid (1, 500 mg, 3.64 mmol) and formamide (2.5 equiv) were mixed and irradiated at
400 W for 15 min, the reaction was monitored by TLC. The reaction mixture was cooled to give the
crude compound 3c which was crystallized from ethanol; Mp 217–219 °C; Yield 95%; Rf 0.63
(CH2Cl2); eluent CH2Cl2; 1H-NMR (CDCl3) δ (ppm): 7.49 (m, 1H, H-Aromatic), 7.64 (d, 1H, J = 8.2 Hz,
H-Aromatic), 7.78 (m, 1H, H-Aromatic), 8.07 (s, 1H, H-Aromatic), 8.10 (d, 1H, J = 8.2 Hz,
13
H-Aromatic), 12.29 (br s, 1H, NH). C-NMR (CDCl3) δ(ppm): 121.72 (C-Aromatic), 125.46, 126.88,
127.39, 133.98, 145.66 (CH-Aromatic), 147.31 (C-Aromatic), 161.63 (CO).

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3.3. Synthesis of Propargylated Quinazolines
The appropriate quinazolin-4-one 3a–c (2 mmol) was dissolved in dry DMF (2.5 mL); KOt-Bu
(1.1 equiv) was added. The mixture was stirred for 15 min at room temperature. Afterwards, propargyl
bromide (2.5 mmol) was added dropwise to the mixture. The reaction was performed for
15 min at room temperature. The reaction mixture was diluted with water (10 mL) and extracted with
ethyl acetate (2 × 20 mL); the organic phase was dried over Na2SO4 and evaporated under vacuum.
The crude products were purified by column chromatography using CH2Cl2/MeOH = 99:1, v/v as eluent.
2-Phenyl-4-(prop-2-ynyloxy)quinazoline (5a). Yield 58%; Rf 0.80; eluent CH2Cl2; 1H-NMR
(CDCl3) δ 2.09 (s, 1H, CCH), 5.28 (s, 2H, -CH2-N), 7.49–8.60 (m, 9H, H-quinazoline, H-Aromatic).
13C-NMR (CDCl3) δ 29.93 (-CH2-), 53.26 (CH-alkyne), 75.59 (C-alkyne), 121.17 (C-Aromatic)
126.17–135.07 (CH-Aromatic), 128.94, 148.86, 152.19 (C-Aromatic), 162.13 (CO).
2-Methyl-3-(prop-2-ynyl)quinazolin-4-one (4b). Yield 76%; Rf 0.75; eluent CH2Cl2; 1H-NMR (CDCl3)
δ 2.32 (s, 1H, CCH), 2.76 (s, 3H, CH3-Aromatic), 4.94 (s, 2H, -CH2-N), 7.48–8.27 (m, 9H,
H-quinazoline). 13C-NMR (CDCl3) δ 22.81 (-CH3), 33.13 (-CH2-), 72.66 (CH-alkyne), 77.06
(C-alkyne), 120.21(C-Aromatic), 126.71, 134.63, 143.14, 145.06 (CH-Aromatic), 147.10, 153.72
(C-Aromatic), 161.32 (CO).
3-(Prop-2-ynyl)quinazolin-4-one (4c). Yield 80%; Rf 0.40; eluent CH2Cl2; 1H-NMR (CDCl3) δ 2.50 (s,
1H, CCH), 4.83 (s, 2H, -CH2-N), 7.47–8.30 (m, 9H, H-quinazoline). 13C-NMR (CDCl3) δ (ppm):
29.08 (-CH2-), 71.58 (CH-alkyne), 77.33 (C-alkyne), 120.18 (C-Aromatic), 126.43, 134.26, 142.98,
145.32 (CH-Aromatic), 146.89, 151.62 (C-Aromatic), 162.06 (CO).
3.4. Synthesis of 1,2,3-Triazol-4-yl substituted O-, N-Quinazolines
Propargylated quinazolines 5a/4b–c (1 mmol), alkyl azide (sugar or pseudosugar, 2.5 mmol) and
Et3N (1.1 mmol) were mixed with CuI (0.1 equiv). For homogenization, the reaction mixture was
dissolved in dry MeCN and stirred for 5 min. Then, the solvent was removed under vacuum. The
mixture was subjected to microwave irradiation at the power level 400 W for 2 min. The residue was
purified on silica gel using CH2Cl2 as eluent.
4-((1-(2,3,5-Tri-O-benzoyl-β-D-ribofuranos-1-yl)1H-1,2,3-triazol-4-yl)methoxy)-2-phenylquinazoline
(6a). Yield 95%; Rf 0.63; eluent CH2Cl2; 1H-NMR (CD Cl3) δ 4.48 (m, 1H, H5'), 4.64 (m, 1H,H5'), 4.75
(m, 1H,H4'), 5.70 (s, 2H, -CH2-), 6.05 (dd, 1H, J = 8.2 Hz, H3'), 6.21 (dd, 1H, J = 8.2 Hz, H2'), 6.32 (d,
1H, H1'), 7.14–7.44 (m, 10H, H-Aromatic) 7.65–7,81 (m, 12H, H-Aromatic), 7.62 (s, 1H, H-Triazole),
8.83–8.88 (m, 2H, H-Aromatic). 13C-NMR (CDCl3) δ 57.21, 61.07 (CH2), 69.13(C5'), 72.81(C2'),
78.72(C3'), 87.72 (C4'), 112.58(C1'), 123.30, 126.59, 127.91, 128.44–133.88 (CH-Aromatic),
135.68–158.34 (C-Aromatic), 163.12, 164.45 (CO). ESI-MS(M+H)+, m/z calcd for C43H33N5O8
748.75, found 748.90.
2-((4-((2-Phenylquinazolin-4-yloxy)methyl)-1,2,3-triazol-1-yl)methoxy)ethylacetate (6b). Yield 88; Rf
1
0.62; eluent CH2Cl2; H-NMR (CDCl3) δ 1.80 (s, 3H, -CO-CH3), 3.63 (t, 2H, -CH2-O), 4.35 (t, 2H,

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-CH2-O-CO), 4.51 (s, 2H, N-CH2-Triazole), 5.88 (s, 2H, O-CH2-Triazole), 7.45 (m, 4H, H-Aromatic),
7.73 (m, 2H, H-Aromatic), 7.84 (s, 1H, H-Triazole), 8.11 (dd, 1H, H-Aromatic), 8.54(dd, 2H,
H-Aromatic). 13C-NMR (CDCl3) δ 20.42(CH3), 49.13 (CH2-quinazoline), 59.78, 62.62 (-OCH2CH2O-),
67.69 (-O-CH2-N<), 123.51–133.80 (-CH-Aromatic), 142.13,146.46, 152.22 (C-Aromatic), 162.43,
(CO-Aromatic),172.12 (CO-Ester). ESI-MS(M+H)+, m/z calcd for C22H21N5O4 420.43, found 420.40.
4-(4-((2-Phenylquinazolin-4-yloxy)methyl)-1,2,3-triazol-1-yl)butylacetate (6c). Yield 83%; Rf 0.68;
1
eluent CH2Cl2; H-NMR (CDCl3) δ 1.56 (s, 3H, -CO-CH3), 1.92 (m, 4H, -CH2-CH2-), 3.97 (t, 2H,
J = 6.3 Hz,-CH2-N(Triazole)), 4.29 (t, 2H, J = 7.2 Hz, -CH2-O-CO), 5.85 (s, 2H, O-CH2-C(Triazole)),
7.46 (m, 4H, H-Aromatic), 7.72 (m, 2H, H-Aromatic), 7.93 (s, 1H, H-Triazole), 8.10 (dd, 1H,
H-Aromatic), 8.56 (dd, 2H, H-Aromatic).13C-NMR (CDCl3) δ 18.61(CH3), 23.38, 24.71 (-CH2-CH2-)
47.62(-CH2-quinazoline), 57.67 (CH2-N(Triazole)), 61.06 (CH2-O), 123.59–133.77 (CH-Aromatic),
142.13, 146.46, 152.22 (C-Aromatic),163.86, (CO-Aromatic), 168.70 (CO-Ester). ESI-MS (M+H)+,
m/z calcd for C23H23N5O3 418.46, found 418.60.
3-((1-(2,3,5-Tri-O-benzoyl-β-D-ribofuranos-1-yl)-1,2,3-triazol-4-yl)methyl)-2-methylquinazolin-4-one
1
(6d). Yield 83%; Rf 0.60; eluent CH2Cl2; H-NMR (CDCl3) δ 2.76 (s, 3H, -CH3), 4.54 (m, 1H, H5'),
4.65 (m, 1H, H5'), 4.81 (m, 1H, H4'), 5.23 (s, 2H, -CH2-), 6.10 (dd, 1H, J = 8.6 Hz, H3'), 6.19 (dd, 1H,
J = 8.6 Hz, H2'), 6.31(d, 1H, H1'), 7.23–7,40(m, 13H, H-Aromatic), 7.57(s, 1H, H-Triazole), 8.62–7.86
(m, 5H, H-Aromatic), 7.88 (m, 1H, H-Aromatic).13C-NMR (CDCl3) δ 23.67(CH3), 39.45, 63.75(CH2),
71.70 (C5'), 75.22 (C2'), 81.13 (C3'), 90.34 (C4'), 117.84 (C1'), 124.07–134.35 (CH-Aromatic),
140.73–159.53 (C-Aromatic), 162.51, 163.58 (CO). ESI-MS(M+H)+, m/z calcd for C38H31N5O8
686,68, found 686.50.
2-((4-((2-Methyl-4-oxoquinazolin-3-yl)methyl)-1,2,3-triazol-1-yl) methoxy) ethylacetate (6e). Yield
1
87%; Rf 0.59; eluent CH2Cl2; H-NMR (CDCl3) δ 1.9(s, 3H, -CO-CH3), 2.84 (s, 3H, Aromatic-CH3),
3.64 (t, 2H, -CH2-O), 4.35 (t, 2H, -CH2-O-CO), 4.52 (s, 2H, N-CH2-Triazole), 5.33 (s, 2H,
O-CH2-Triazole), 7.34–7.55 (m, 3H, H-Aromatic), 7.78 (s, 1H, H-Triazole), 8.13 (m, 1H, H-Aromatic).
13C-NMR (CDCl3) δ 20.23, 23.86 (CH3), 39.59 (CH2-quinazoline), 49.04, 62.16 (OCH2CH2O), 78.77
(O-CH2-N), 120.24–134.34 (CH-Aromatic), 143.00, 147.35, 154.36 (C-Aromatic), 162.01 (CO-Aromatic),
170.25 (CO-Ester). ESI-MS(M+H)+, m/z calcd for C17H19N5O4 358.36, found 358.40.
4-(4-((2-Methyl-4-oxoquinazolin-3-yl)methyl)-1,2,3-triazol-1-yl)butylacetate (6f). Yield 86%; Rf 0.60;
1
eluent CH2Cl2; H-NMR (CDCl3) δ 1.55 (s, 3H, -CO-CH3), 1.90 (m, 4H,-CH2-CH2-), 2.83 (s, 3H,
Aromatic-CH3), 3.99 (t, 2H, J = 6.2Hz, -CH2-N(Triazole)), 4.27 (t, 2H, J = 7.2Hz, -CH2-O-CO), 5.29
(s, 2H, O-CH2-C(Triazole)), 7.20–7,52 (m, 3H, H-Aromatic), 7.63 (s, 1H, H-Triazole), 8.17 (m, 1H,
H-Aromatic). 13C-NMR (CDCl3) δ (ppm): 20.88, 23.74 (CH3), 25.67, 26.87 (CH2-CH2) 39.72
(CH2-quinazoline), 49.91 (CH2-N(Triazole)), 63.32 (CH2-O), 123.89–134.46(CH-Aromatic), 142.93,
147.42, 154.44 (C-Aromatic), 162.71, (CO-Aromatic), 168.70 (CO-Ester). ESI-MS(M+H)+, m/z calcd
for C18H21N5O3 356.39, found 356.40.
3-((1-(2,3,5-Tri-O-benzoyl-β-D-ribofuranos-1-yl)-1,2,3-triazol-4-yl)methyl)quinazolin-4-one
(6g).
1
Yield 84%; Rf 0.60; eluent CH2Cl2; H-NMR (CDCl3) δ (ppm): 4.68 (m, 1H, H5'), 4.75 (m, 1H, H5'),

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4.91 (m, 1H, H4'), 5.30 (s, 2H, -CH2-), 6.16 (dd, 1H, J = 7.8 Hz, H3'), 6.26 (dd, 1H, J = 7.8 Hz, H2'),
6.38(d, 1H, H1'), 7.27–7.40 (m, 13H, H-Aromatic), 7.69 (s, 1H, H-Triazole), 7.87–8.08 (m, 5H,
H-Aromatic), 7.30 (m, 1H, H-Aromatic). 13C-NMR (CDCl3) δ (ppm): 41.46, 63.68 (CH2), 71.65 (C5'),
75.20 (C2'), 81.24 (C3'), 90.42 (C4'), 122 (C1'), 123.56–134.36 (CH-Aromatic), 142.46–160.90
(C-Aromatic), 164.98, 166.05 (CO). ESI-MS(M+H)+, m/z calcd for C37H29N5O8 672.65, found 672.80.
2-((4-((4-Oxoquinazolin-3-yl)methyl)-1,2,3-triazol-1-yl)methoxy)ethylacetate (6h). Yield 90%; Rf 0.57;
1
eluent CH2Cl2; H-NMR (CDCl3) δ 1.9 (s, 3H, -CO-CH3), 3.64 (t, 2H,-CH2-O), 4.35 (t, 2H, -CH2-O-
CO), 4.52 (s, 2H, N-CH2-Triazole), 5.33 (s, 2H, O-CH2-Triazole), 7.21-7.42 (m, 3H, H-Aromatic),
13
7.77 (s, 1H, H-Triazole), 8.18–8.30 (m, 2H, H-Aromatic). C-NMR (CDCl3) δ 20.63 (CH3), 41.63
(CH2-quinazoline), 49.15, 62.19 (-OCH2CH2O-), 79.11 (-O-CH2-N<), 121.94–134.44 (CH-Aromatic),
142.43, 146.30, 148.14 (C-Aromatic), 160.99 (CO-Aromatic), 170.34 (CO-Ester). ESI-MS (M+H)+,
m/z calcd for C16H17N5O4 344.34, found 344.10.
4-(4-((4-Oxoquinazolin-3-yl)methyl)-1,2,3-triazol-1-yl)butylacetate (6i). Yield 89%; Rf 0.60; eluent
CH2Cl2; 1H-NMR (CDCl3) δ 1.55 (s, 3H, -CO-CH3), 1.90 (m, 4H,-CH2-CH2-), 3.40 (t, 2H, J = 6.3 Hz,
-CH2-N(Triazole)), 4.28 (t, 2H, J = 7.2 Hz, -CH2-O-CO), 5.20 (s, 2H, O-CH2-C(Triazole)), 7.20 (m,
1H, H-Aromatic), 7.65 (s, H, H-Aromatic, H-Triazole), 8.19–8.28 (m, 2H, H-Aromatic). 13C-NMR
(CDCl3) δ 20.88 (CH3), 25.66, 26.87 (CH2-CH2) 39.72(CH2-quinazoline), 49.91 (CH2-N(Triazole)),
63.32 (CH2-O), 123.89–134.46 (CH-Aromatic), 142.93, 147.42, 154.44 (C-Aromatic), 162.71,
(CO-Aromatic), 168.70 (CO-Ester). ESI-MS(M+H)+, m/z calcd for C17H19N5O3 342.36, found 342.33.
3.4.1. Benzoyl Group Deprotection
The compound (6a,d,g, 1 mmol) was dissolved in dry methanol (2.5 mL). NaOMe (1 eq) was added
to the solution with stirring for 30 min at room temperature. The neutralization was performed with
AmberliteIR120 hydrogen form. After, filtration and evaporation the residue was purified by silica gel
flash column chromatography.
3.4.2. Acetyl Group Deprotection
A solution of (6b,c,e,f,h,i, 1 mmol) in dry methanol (2.5 mL) was treated with 1 eq of K2CO3. The
reaction mixture was stirred at room temperature for 15 min. The deprotected compound was purified
by silica gel flash column chromatography.
4-((1-(β-D-Ribofuranos-1-yl)-1,2,3-triazol-4-yl)methoxy)-2-phenylquinazoline (7a). Yield 98%; Rf 0.56;
1
eluent CH2Cl2/MeOH = 95/5: v/v; H-NMR (DMSO-d6) δ 2.50 (d, 2H, -CH2-), 3.35–3.65 (m, 3H, -OH),
4.18 (m, 1H, H5'), 4.42 (m, 1H,H5'), 4.91 (m, 1H,H4'), 5.88 (s, 2H, -CH2-), 5.28 (dd, 1H, J = 8.2 Hz, H3'),
5.71 (dd, 1H, J = 8.2 Hz, H2'), 6.01 (d, 1H,H1'),. 7.55 (m, 4H, H-Aromatic) 7.97 (m, 2H, H-Aromatic),
8.25 (s, 1H, H-Triazole), 8.58 (m, 3H, H-Aromatic). 13C-NMR (DMSO-d6) δ 59.81 (CH2), 61.31 (C5'),
70.36 (C2'), 75.08 (C3'), 85.89 (C4'), 92.10 (C1'), 114.38–130.83 (CH-Aromatic), 134.36–158.82
(C-Aromatic), 165.74 (CO). ESI-MS(M+H)+, m/z calcd for C22H21N5O5 436.43, found 436.30.

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2-((4-((2-Phenylquinazolin-4-yloxy)methyl)-1,2,3-triazol-1-yl)methoxy)etanol (7b). Yield 86%; Rf 0.43;
1
eluent CH2Cl2/MeOH, 95/5: v/v; H-NMR (DMSO-d6) δ 3.63 (t, 4H,-CH2-O), 4.24 (s, 2H,
N-CH2-Triazole), 4.65 (t, 1H, -OH), 5.28 (s, 2H, O-CH2-Triazole), 7.67 (m, 4H, H-Aromatic), 7.67 (m,
2H, H-Aromatic), 7.96 (s, 1H, H-Triazole), 8.54 (dd, 3H, H-Aromatic). 13C-NMR (DMSO-d6) δ 20.32
(CH3), 49.13 (CH2-quinazoline), 59.78 (CH2OH), 62.62 (OCH2), 66.87 (O-CH2-N), 124.50–134.20
(CH-Aromatic), 141.7–153.60 (C-Aromatic), 161.32, (CO-Aromatic). ESI-MS(M+H)+, m/z calcd for
C20H19N5O3 378.40, found 378.30.
4-(4-((2-Phenylquinazolin-4-yloxy)methyl)-1,2,3-triazol-1-yl)butan-1-ol (7c). Yield 88%; Rf 0.44;
1
eluent CH2Cl2/MeOH = 95/5, v/v; H-NMR (DMSO-d6) δ 1.45–1.86 (m, 4H,-CH2-CH2-), 2.50 (t, 1H,
-OH), 4.38 (s, 2H, -CH2OH), 4.39 (t, 2H, J = 6.3Hz, -CH2-N(Triazole)), 5.85 (s, 2H, N-CH2-Triazole),
7.54 (m, 4H, H-Aromatic), 7.87 (m, 3H, H-Aromatic), 8.32 (s, 1H, H-Triazole), 8.57 (m, 2H, H-Aromatic).
13C-NMR (DMSO-d6) δ 26.56–29.19 (CH2-CH2) 47.62 (CH2-quinazoline), 57.67 (CH2-N(Triazole)),
61.06 (CH2-O), 114.41–130.80 (CH-Aromatic), 134.30–158.80 (C-Aromatic), 165.47 (CO-Aromatic).
ESI-MS(M+H)+, m/z calcd for C21H23N5O2 376.44, found 376.50.
3-((1-(β-D-Ribofuranos-1-yl)-1,2,3-triazol-4-yl)methyl)-2-methylquinazolin-4-one (7d). Yield 97%;
1
Rf 0.60; eluent CH2Cl2/MeOH = 95/5, v/v; H-NMR (DMSO-d6) δ 2.74 (s, 3H, -CH3), 3.56–4.22
(m, 3H, -OH), 4.67 (m, 1H, H5'), 4.98 (m, 1H, H5'), 5.22 (m, 1H, H4'), 5.41 (s, 2H, -CH2-), 6.10 (dd,
1H, J = 8.6 Hz, H3'), 5.62 (dd, 1H, J = 8.6 Hz, H2'), 6.01 (d, 1H, H1'), 7.46–7.60 (m, 2H, H-Aromatic),
7.83 (m, 1H, H-Aromatic), 8.11 (s, 1H, H-Triazole), 8.32 (m, 1H, H-Aromatic). 13C-NMR (DMSO-d6)
δ(ppm): 23.67 (CH3), 58.81 (CH2), 61.23 (C5'), 70.28 (C2'), 74.94 (C3'), 85.83 (C4'), 92.03 (C1'),
119.80–126.52 (CH-Aromatic), 134.45–155.00 (C-Aromatic), 160.90 (CO). ESI-MS (M+H)+, m/z
calcd for C17H19N5O5 374.36, found 374.30.
2-((4-((2-Methyl-4-oxoquinazolin-3-yl)methyl)-1,2,3-triazol-1-yl)methoxy)ethanol (7e). Yield 95%;
1
Rf 0.40; eluent CH2Cl2/MeOH = 95/5, v/v; H-NMR (DMSO-d6) δ 2.74 (s, 3H, -CH3), 3.39 (t, 2H,
-CH2-O), 3.64 (t, 2H, -CH2-O), 4.50 (s, 2H, N-CH2-Triazole), 4.63 (t, 1H, -OH), 5.21 (s, 2H, O-CH2-
Triazole), 7.46–7,65 (m, 2H, H-Aromatic), 7.82 (s, 1H, H-Triazole), 8.07 (m, 2H, H-Aromatic).
13C-NMR (DMSO-d6) δ 22.98 (CH3), 40.31 (CH2-quinazoline), 59.78 (CH2OH), 62.62 (OCH2), 80.27
(O-CH2-N), 119.83–134.42 (CH-Aromatic), 142.04, 147.03, 155.03 (C-Aromatic), 160.92 (CO-Aromatic).
ESI-MS(M+H)+, m/z calcd for C15H17N5O3 316.33, found 316.40.
4-(4-((2-Methyl-4-oxoquinazolin-3-yl)methyl)-1,2,3-triazol-1-yl)butan-1-ol (7f). Yield 90%; Rf 0.39;
1
eluent CH2Cl2/MeO = 95/5, v/v; H-NMR (DMSO-d6) δ (ppm): 1.43–1.88 (m, 4H, -CH2-CH2-), 2.61
(s,3H, -CH3), 2.72 (t, 1H, -OH), 4.37 (s, 2H, -CH2OH), 4.40 (t, 2H, J = 6.3 Hz, -CH2-N(Triazole)),
5.56 (s, 2H, N-CH2-Triazole), 7.58–7.69 (m, 2H, H-Aromatic), 7.87 (s, 1H, H-Triazole), 8.17(m, 2H,
H-Aromatic). 13C-NMR (DMSO-d6) δ 22.96 (CH3), 26.48, 29.19 (CH2-CH2) 40.30 (CH2-quinazoline),
49.31 (CH2-N(Triazole)), 59.94 (CH2-O), 119.82–134.41 (CH-Aromatic), 142.23, 147.03, 155.01
(C-Aromatic), 160.91 (CO-Aromatic). ESI-MS(M+H)+, m/z calcd for C16H19N5O2 314.35, found 314.30.
3-((1-(β-D-Ribofuranos-1-yl)-1,2,3-triazol-4-yl)methyl)quinazolin-4-one (7g). Yield 98%; Rf: 0.62;
1
eluent CH2Cl2/MeOH = 95/5, v/v; H-NMR (DMSO-d6) δ 3.52–4.33 (m,3H,-OH), 4.59 (m, 1H, H5'),

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4.70 (m, 1H, H5'), 4.88 (m, 1H, H4'), 5.28 (s, 2H, -CH2-), 5.66 (dd, 1H, J = 7.8 Hz, H3'), 5.73 (dd, 1H,
J = 7.8 Hz, H2'), 6.20 (d, 1H, H1'),. 7.44–7.58 (m, 3H, H-Aromatic), 7.63 (s, 1H, H-Triazole), 7.92 (m,
2H, H-Aromatic). 13C-NMR (75 MHz, DMSO-d6) δ 40.86 (CH2), 61.28 (C5'), 70.31 (C2'), 74.97 (C3'),
85.85 (C4'), 92.02 (C1'), 121.53–132.23 (CH-Aromatic), 134.44, 142.60, 147.83 (C-Aromatic), 159.84
(CO). ESI-MS(M+H)+, m/z calcd for C16H17N5O5 360.34, found 360.42.
2-((4-((4-Oxoquinazolin-3-yl)methyl)-1,2,3-triazol-1-yl)methoxy)ethanol (7h). Yield 93%; Rf: 0.39;
1
eluent CH2Cl2/MeOH = 95/5, v/v; H-NMR (DMSO-d6) δ 3.64 (m, 4H, -CH2-O), 4.23 (t, 1H, -OH),
4.56 (s, 2H, N-CH2-Triazole), 5.40 (s, 2H, O-CH2-Triazole), 7.62–7.79 (m, 3H, H-Aromatic), 7.80 (m, 2H,
13
H-Triazole, H-Aromatic), 8.33 (s, 1H, H-Aromatic). C-NMR (DMSO-d6) δ 52.20 (CH2-quinazoline),
59.70 (CH2OH), 70.97 (OCH2), 78.21 (O-CH2-N), 121.45–134.41 (CH-Aromatic), 142.00, 147.82,
155.12 (C-Aromatic), 159.84 (CO-Aromatic). ESI-MS(M+H)+, m/z calcd for C14H15N5O3 302.30,
found 302.30.
4-(4-((4-Oxoquinazolin-3-yl)methyl)-1H-1,2,3-triazol-1-yl)butan-1-ol (7i). Yield 94%; Rf: 0.43; eluent
CH2Cl2/MeOH = 95/5, v/v; 1H-NMR (CDCl3) δ 1.39–1.87 (m, 4H,-CH2-CH2-), 2.56 (t, 1H, -OH), 4.36
(s, 2H, -CH2OH), 4.43 (t, 2H, J = 6.3 Hz, -CH2-N(Triazole)), 5.32 (s, 2H, N-CH2-Triazole), 7.58–7.69
13
(m, 2H, H-Aromatic), 7.87 (s, 1H, H-Triazole), 8.17 (m, 2H, H-Aromatic). C-NMR (DMSO-d6) δ
26.49, 29.18 (CH2-CH2) 40.94 (CH2-quinazoline), 49.30 (CH2-N(Triazole)), 59.94 (CH2-O), 121.54–127.19
(CH-Aromatic), 142.20, 147.81, 147.815 (C-Aromatic), 159.84, (CO-Aromatic). ESI-MS(M+H)+, m/z
calcd for C15H17N5O2 300.33, found 300.30.
4. Conclusions
In summary, the synthesis of a series of 1,2,3-triazole-4-yl-quinazoline derivatives starting from
anthranilic acid was performed efficiently using click chemistry under microwave irradiation. None of
the compounds selected showed significant anti-HCV activity.
Acknowledgments
This project was supported by the CNRST Research program RS 2011/01. We gratefully
acknowledge Ananthan Sam, Southern Research Institute Birmingham, Alabama, AL, USA, for
helpful discussion.
Author Contributions
J. W. Engels, H. B. Lazrek and M. Taourirte supervised and designed the study. A. Ouahrouch
performed the experiments, analysed the data and wrote the paper. S. Benjelloun performed the
antiviral activity.
Conflicts of Interest
The authors declare no conflict of interest.

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Sample Availability: Samples of the compounds 7a–i are available from the authors.
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