Click chemistry: Studies on the synthesis of novel fluorous tagged triazol-4-yl substituted quinazoline derivatives and their biological evaluation - Theoretical and experimental validation

Article abstract of DOI:10.1016/j.ejmech.2009.09.027

The formation of N- and O-propargylated quinazoline derivatives 2, 3 from quinazol-4-ones 1 was theoretically predicted by optimizations at B3LYP/6-31G* level, analysed kinetically and thermodynamically. Theoretical predictions are validated by experiment to observe the trends and found deviation. Thus, compound 1 was propargylated in basic media to obtain compound 2 and 3 in definite proportions. Each compound was further subjected to [3 + 2] cycloaddition using perfluoroalkyl azides through Click reaction under Sharpless conditions, and obtained a series of novel perfluoroalkyl-1H,1,2,3-triazol-4-yl substituted quinazolines 4, 5, and 6. All the compounds were screened for antimicrobial activity and identified potential compounds.

Full text of DOI:10.1016/j.ejmech.2009.09.027

European Journal of Medicinal Chemistry 45 (2010) 78–84
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Click chemistry: Studies on the synthesis of novel fluorous tagged triazol-4-yl
substituted quinazoline derivatives and their biological evaluation – Theoretical
and experimental validation
,
d
P. Mani Chandrika a, T. Yakaiah b, G. Gayatri c, K. Pranay Kumar d, B. Narsaiah b , U.S.N. Murthy ,
*
A. Raghu Ram Rao e
a Medicinal Chemistry Research Division, University College of Pharmaceutical Sciences, Kakatiya University, Warangal, India
b Fluoroorganic Division, Indian Institute of Chemical Technology, Tarnaka, Hyderabad, India
c Molecular Modelling Division, Indian Institute of Chemical Technology, Tarnaka, Hyderabad, India
d Biology Division, Indian Institute of Chemical Technology, Tarnaka, Hyderabad, India
e University Institute of Pharmaceutical Sciences, Punjab University, Chandigarh, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The formation of N- and O-propargylated quinazoline derivatives 2, 3 from quinazol-4-ones 1 was
theoretically predicted by optimizations at B3LYP/6-31G* level, analysed kinetically and thermody-
namically. Theoretical predictions are validated by experiment to observe the trends and found devia-
tion. Thus, compound 1 was propargylated in basic media to obtain compound 2 and 3 in definite
proportions. Each compound was further subjected to [3 þ 2] cycloaddition using perfluoroalkyl azides
through Click reaction under Sharpless conditions, and obtained a series of novel perfluoroalkyl-1H,1,2,3-
triazol-4-yl substituted quinazolines 4, 5, and 6. All the compounds were screened for antimicrobial
activity and identified potential compounds.
Received 24 March 2009
Received in revised form
22 August 2009
Accepted 10 September 2009
Available online 30 September 2009
Keywords:
Quinazolines
Propargylation
Perfluoroalkyl azides
Click reaction
Ó 2009 Published by Elsevier Masson SAS.
Selective cyclisation
Sharpless conditions
1. Introduction
for the synthesis of fluorinated molecules in order to find a poten-
tial pharmacophore.
The Quinazoline nucleus features in many alkaloids and is
known to show a wide range of biological activity [1–3]. A few non-
classical quinazoline analogues of folic acid have remarkable
antibacterial and antimalarial effects and most prominent is tri-
metrexate [4]. The specific 3H-quinazolin-4-one derivatives known
in the art as anti-convulsant [5], CNS depressant [6], muscle
relaxant [7], anti-neoplastic [8–10] and antimicrobial agents
[11–21]. It is also known that fluorine [22] or trifluoromethyl
[23,24] group at an appropriate position in the molecule alters the
properties of molecule by promoting activity due to high lipid
solubility and enhancement of transport mechanism. The per-
fluoroalkyl triazoles [25,26], perfluoroalkyl tetrazolo-5-ones [27]
and other fluoroalkyl derivatives [28–30] also found to show
promising biological activity. Therefore, there is a growing demand
In continuation of our efforts toward synthesis of potential
molecules such as quinazolines [31–34], pyrido pyrimidines [35],
pyrimido[1,2-b] indazoles [36,37], we have synthesized a series of
O-propargylated quinazolines 2, N-propargylated quinazolines 3,
perfluoroalkyl-1H,1,2,3-triazol-4-yl substituted O-/N-quinazolines
4, 5, 6 and screened for antimicrobial activity. Computational
studies were carried out to unravel the observed trends. The
prediction for formation of isomers 2 and 3 is validated by exper-
iment in basic media to observe the trend and found deviation.
Each isomer is further subjected to [3 þ 2] cycloaddition reaction
using perfluoroalkyl azides through Click reaction [38,39] under
Sharpless conditions. All the final compounds were screened for
antimicrobial activity and identified potential compounds.
2. Chemistry
The 2-substituted quinazol-4-ones 1 were initially propargy-
lated using propargyl bromide in acetone and potassium carbonate
* Corresponding author. Tel.: þ91 40 27193630; fax: þ91 40 27193185.
E-mail address: narsaiah_1984@yahoo.co.in (B. Narsaiah).
0223-5234/$ – see front matter Ó 2009 Published by Elsevier Masson SAS.
doi:10.1016/j.ejmech.2009.09.027

P. Mani Chandrika et al. / European Journal of Medicinal Chemistry 45 (2010) 78–84
79
Table 1
Preparation of compounds 1.
under reflux conditions, obtained two isomers 2, 3 in definite
proportions. The ratio of each isomer is evaluated based on the
substituent present in second position. The CF3 substituent
Entry
Compd. no.
R
m.p. ꢀC
Yield (%)
promoted O-propargylated isomer
2 and phenyl substituent
1
2
3
1a [31]
1b [42]
1c
C6H5
CF3
2,6-C6H3F2
226
250
231
84
85
81
favored N-propargylated isomer 3 as major products. However, the
2,6-difluorophenyl substituent gave exclusively N-propargylated
isomer 3. The role of CF3 is consistent with the earlier reports
[40–42] whereas role of phenyl substituent is differed. The change
in ratio and mode of formation of products may be due to change in
reaction medium and base. Each isomer is separated and
characterized.
Table 2
Preparation of O-, N-propargylated quinazoline derivatives 2a–b and 3a–c.
Entry
Compd no.
R
m.p. ꢀC
Yield (%)
The isomers
2 and 3 were independently reacted with
1
2
3
4
5
2a [42]
3a [42]
2b [42]
3b [42]
3c
C6H5
C6H5
CF3
CF3
130
174
101
98
39
50
52
32
86-
perfluoroalkyl azides in THF using copper (I) iodide as catalyst to
give perfluoroalkyl-1H,1,2,3-triazol-4-yl substituted O-, N-quina-
zoline derivatives 4a–d, 5a–b and 6a–f. Compound 2 gave product
4 as major and 5 as minor however compound 3 gave exclusive
product 6. The reaction is considered to take place via 1,3-dipolar
cycloaddition of azide to alkyne, through a preformed copper
acetylide complex formation [43,44]. The reactions are drawn in
Scheme 1 and products are tabulated in Tables 1–3.
2,6-F2C6H3
133
calculations are done using Polarized Continuum (overlapping
spheres) Model (PCM) and all the calculations are done using
G03W program package. The reactivity and feasibility of products
with different yields are explained based on the thermodynamic
and kinetic stabilities of the products. The transition state and
product structures for all the systems along with the activation and
reaction energy values (in kcal/mol) are depicted in Fig. 1.
3. Theoretical interpretations based on computational
studies of compounds 2a–c, 3a–c, 4a, 4c, 4e, 6a, 6c, 6e
From the Fig. 1 (3a–c) it is observed that the substituents CF3, Ph
and 2,6-F2Ph in second position thermodynamically favor N-
Computational studies were carried out to unravel the observed
trends. Optimizations of the reactants, products and transition
states have been carried out at B3LYP/6-31G* level. Solvent
propargylated quinazolines
3
and is consistent with the
O
O
O
Br
N
R
a
N
NH
+
+
N
N
R
N
R
1
3
2
R= C6H5, CF3, 2,6-C6H3F2
b
CF3(CF2)nCH2CH2N3
NaN3
CF3(CF2)nCH2CH2I
n= 5,7
+
H
N
O
N
O
N
N
(CF2)nCF3
N
c
CF3(CF2)nCH2CH2N3
n= 5,7
+
N
R
N
R
4
+
H
2
R= C6H5, CF3
O
N
N
N
N
R
(CF2)nCF3
N
5
O
N
O
N
H
c
N
+
CF3(CF2)nCH2CH2N3
n= 5,7
(CF2)nCF3
N
N
N
R
N
R
3
6
,
2,6-C6H3F2
R= C6H5, CF3
Scheme 1. Reagents & conditions: a) K2CO3, NaI acetone, reflux. b) Acetone, water, reflux. c) CuI, THF, room temperature.

80
P. Mani Chandrika et al. / European Journal of Medicinal Chemistry 45 (2010) 78–84
Table 3
Table 4
Activation Ez, reaction energy Er values in kcal/mol of 4a, c, e and 6a, c, e.
Perfluoroalkyl-1H,1,2,3-triazol-4-yl substituted O-, N-quinazolines (4a–d), (5a, 5b),
(6a–f).
Compd. no.
Conformation
D
Ez
DEr
Entry
Compd no.
R
n
m.p. ꢀC
Yield (%)
4a
4a
4c
4c
4e
4e
6a
6a
6c
6c
6e
6e
Syn
Anti
Syn
Anti
Syn
Anti
Syn
Anti
Syn
Anti
Syn
Anti
17.00
16.57
16.62
16.44
16.83
16.72
17.64
16.79
19.13
16.74
17.32
17.06
ꢁ70.4
ꢁ73.0
ꢁ72.1
ꢁ73.2
ꢁ70.6
ꢁ73.0
ꢁ70.5
ꢁ76.8
ꢁ69.5
ꢁ75.0
ꢁ70.7
ꢁ74.7
1
2
3
4
5
6
7
8
4a
5a
4b
5b
4c
4d
6a
6b
6c
6d
6e
6f
C6H5
C6H5
C6H5
C6H5
CF3
CF3
C6H5
C6H5
5
5
7
7
5
7
5
7
5
7
5
7
118
125
128
149
93
105
241
160
144
156
99
46
40
47
38
85
86
85
88
83
87
81
80
9
2,6-C6H3F2
2,6-C6H3F2
CF3
10
11
12
CF3
116
experimental results except with CF3. Kinetic stabilities suggest
that, phenyl substituent favor O-propargylated quinazolines 2, CF3
and 2,6-F2Ph substituents favor N-propargylated quinazolines is
inconsistent with the experimental results except with the 2,6-
difluorophenyl substituent. This may be attributed to the small
difference in the activation energies 0.4–1.3 kcal/mol and large
difference in reaction energies 6–7 kcal/mol for CF3 and Ph which
promote uneven trends. In case of 2,6-F2Ph substituent, the
difference in reaction energies of two isomers is almost 10 kcal/mol
which has resulted in exclusive formation of N-propargylated
quinazoline derivative. Further [3 þ 2] cycloaddition reaction
between propargylated quinazolines and alkyl azides are analysed.
Theoretical studies on such molecules using Cu as catalyst, along
with the mechanism are well established [45]. The alkyl tagged
bulky group on the azide nitrogen is replaced with simple alkyl
(Bacillus subtilis, Staphylococcus aureus, Staphylococcus epidermidis)
and gram-negative (Pseudomonas aeruginosa, Escherichia coli)
bacteria. Compounds 4c and 5b showed significant activity against
all species of gram-positive and gram-negative bacteria except
E. coli. Compounds 3a, 4a–b, 6a–b and 6d–f showed moderate
activity and 2a, 4d and 6c showed the least activity. The regioisomer
3a is more active than compound 2a and 5b is more active than
compound 4b against all the bacterial species. The compound 4c is
identified as most active compound. The MIC values of the
compounds were compared with those obtained with penicillin and
streptomycin. Compound 4c and 5b are considered as interesting
lead compounds. The details of compounds and their activity profile
against various microorganisms are tabulated in Table 5.
group i.e., ‘C2H5’ for easier computation. Activation energy
reaction energy Er values are in kcal/mol given in Table 4.
D
Ez and
4.2. In vitro antifungal activity assays
D
The in vitro antifungal activity of compounds 2a, 3a, 4a–d, 5b,
6a–f were screened against the fungal strains, viz., Candida albicans
(MTCC 227), Saccharomyces cerevisiae (MTCC 36) and filamentous
fungal cultures like Rhizopus oryzae (MTCC 262), Aspergillus niger
(MTCC 1344), Aspergillus flavus (MTCC 277), Candida rugosa (NCIM
3462) by agar cup diffusion method. The strains were obtained
from the Institute of Microbial Technology, Chandigarh.
Compounds 3a, 6a, 6e showed promising activity against most of
The theoretical results suggest that, the formation of anti
product is more feasible and stable than syn both kinetically and
thermodynamically. This might be mainly due to the steric repul-
sions arising due to the bulky fluorous alkyl tag attached to the
triazole ring.
4. Antimicrobial activity
the fungi at 100 mg/ml. It is found that the inhibition diameter
4.1. In vitro antibacterial assays
increases with concentration. Compound 4d is inactive against all
the fungal cultures except for C. albicans (MTCC 227) and C. rugosa
(NCIM 3462). The regioisomer 5b is more active than 4b and 3a is
more active than 2a. However, all the compounds 2a, 4d and 6c are
Compounds 2a, 3a, 4a–d, 5b, 6a–f were dissolved in acetone and
screened for in vitro antibacterial activity against gram-positive
Fig. 1. Structures of the compounds 2a–c, 3a–c in their Transition State TS and their activation energy (D DEr) respectively in gas (normal) and solvent
Ez) and reaction energy (
(italics) phases respectively. All the energy values are in kcal/mol.

P. Mani Chandrika et al. / European Journal of Medicinal Chemistry 45 (2010) 78–84
81
Table 5
6. Experimental
Minimum inhibitory concentration (MIC in
m
g/ml) of compounds 2a, 3a, 4a–d, 5b,
6a–f against various bacterial microorganisms.
6.1. Chemistry
Entry Compd. no.
Gram-positive strains
Gram-negative strains
6.1.1. General methods
B. subtilis S. aureus S. epidermidis E. coli
P. aeruginosa
Melting points were recorded on Casia-siamia (VMP-AM)
melting point apparatus and are uncorrected. IR spectra were
recorded on a Perkin–Elmer FT-IR 240-C spectrophotometer using
KBr optics. 1H NMR spectra were recorded on Gemini varian
200 MHz, Bruker AV 300 MHz and Unity 400 MHz spectrometer in
DMSO-d6 or CDCl3 using TMS as an internal standard. Electron
impact (EI) and chemical ionisation mass spectra were recorded on
a VG 7070 H instrument at 70 eV. All reactions were monitored by
thin layer chromatography (TLC) on precoated silica gel 60 F254
(mesh); Spots were visualized with UV light. Merck silica gel
(100–200 mesh) was used for chromatography. CHN analyses were
recorded on a Vario EL analyser. Five bacterial test organisms such
as B. subtilis (MTCC 441), S. aureus (MTCC 96), S. epidermidis (MTCC
435), E. coli (MTCC 443) and P. aeruginosa (MTCC 741) were selected
and obtained from the Institute of Microbial Technology,
Chandigarh.
1
2
3
4
5
6
7
8
2a
3a
4a
4b
4c
4d
5b
6a
6b
6c
6d
6e
150
37.5
150
150
18.75
150
37.5
150
150
150
150
150
150
150
37.5
75
150
37.5
75
150
75
75
150
75
150
75
75
15
150
75
75
150
37.5
75
150
150
75
9.375
150
9.375
150
75
150
150
150
75
1.56
6.25
9.375
150
9.375
150
75
150
150
150
75
1.562
3.125
37.5
150
37.5
37.5
75
150
75
75
9
10
11
12
13
14
15
6f
75
3.125
6.25
75
3.125
12.5
Streptomycin
Penicillin
6.25
1.526
Negative control; acetone showed no activity.
Table 6
Zone of Inhibition (in mm) of compounds 2a, 3a, 4a–d, 5b, 6a–f for various fungal cultures at two concentration levels.
Entry
Compd.
C. albicans
g/ml)
S. cerevisiae
g/ml)
R. oryzae
g/ml)
A. niger
g/ml)
A. flavus
g/ml)
C. rugosa
(mg/ml)
(
m
(
m
(
m
(
m
(
m
30
100
30
100
30
100
30
100
30
100
30
100
1
2
3
4
5
6
7
8
2a
3a
4a
4b
4c
4d
5b
6a
6b
6c
6d
6e
7
7
8
7
8
–
8
9
–
7
7
–
7
23.5
10
10
11
10
12
9
12
12
9
10
10
9
9
22
–
9
–
7
–
–
–
8
–
–
–
9
–
24
–
12
9
10
9
–
9
12
9
–
9
–
8
–
–
–
–
–
–
–
–
–
8
–
25
–
12
–
10
9
–
12
10
10
–
9
13
–
7
7
8
7
8
–
8
9
–
7
7
–
7
10
10
11
10
12
9
12
12
9
–
9
–
7
–
–
–
8
–
–
–
9
–
–
12
9
10
9
–
9
12
9
–
9
–
8
–
–
–
–
–
–
–
–
–
8
–
–
12
–
10
9
–
12
10
10
–
9
13
–
9
10
11
12
13
14
10
10
9
12
9
25
12
9
6f
9
Amphotericin-B (50
m
g/ml)
22
Negative control; acetone showed no activity; well or cup method; the concentrations are expressed in mg/ml and inhibitory zone diameters are expressed in mm.
inactive against all fungal cultures except for C. albicans upto
a maximum concentration of 100 g/ml. The compounds 3a and 6e
6.1.1.1. Preparation of 2-phenyl quinazoline-4 (3H)-one (1a). Ref. [31].
m
are identified as most active compounds. The inhibitory zone
diameters of the compounds are compared with those obtained
6.1.1.2. Preparation of 2-(trifluoromethyl) quinazoline-4 (3H)-one
(1b). Ref. [42].
with 50 mg/ml of standard amphotericin. The details of the results
have been tabulated in Table 6.
6.1.1.3. Preparation of (2,6-difluorophenyl) quinazolin-4(3H)-one
(1c). The 2-(2,6-difluorophenyl)-4H-benzo(d) (1,3) oxazin-4-one
(0.5 g, 1.93 mmol) was treated with aqueous ammonia at room
temperature while stirring for 4 h. Excess ammonia was removed
by evaporation and quenched with water. The solid obtained was
filtered and crude product 2-(2,6-difluoro phenylamido) benza-
mide thus formed was refluxed in presence of aq. NaOH for 2 h. The
reaction mixture was neutralized with acid and separated solid
product was filtered, washed with water and dried. The crude
product was purified passing through a column packed with silica
gel (mesh 60/120) and solvents hexane: ethyl acetate (90:10) as
eluents. Yield: 0.42 g (85%); m.p: 234 ꢀC; IR (KBr, cmꢁ1): 1675
(lactam CO), 1553 (C]N), 1457 (C]C); 1H NMR (200 MHz, DMSO-
5. Conclusion
A
series
of
novel perfluoroalkyl-1H-1,2,3-triazol-4-yl
substituted O-/N-quinazolines 4, 5 and 6 was synthesized from
quinazolinones via propargylation followed by Click reaction.
Theoretical interpretations based on computational studies were
calculated for the formation of compounds 2 and 3 and are vali-
dated by experiments. All the compounds were screened against
gram-positive, gram-negative bacterial strains and also fungal
strains. Compounds 4c and 5b showed significant activity against
bacterial strains and compounds 3a, 6a and 6e showed promising
activity against fungi.
d6):
d
7.00–7.18 (t, J ¼ 11.53 Hz, 2H, Ar–H), 7.57–7.77 (quintet,
J ¼ 7.69 Hz, 2H, Ar–H), 7.70–7.82 (quintet, J ¼ 7.69 Hz, 2H, Ar–H),

82
P. Mani Chandrika et al. / European Journal of Medicinal Chemistry 45 (2010) 78–84
8.20–8.30 (d, J ¼ 15.38 Hz, 1H, Ar–H), 12.60 (s, 1H, NH); EIMS, m/z:
259 (Mþ þ 1); IR (KBr): 1675 (CO) cmꢁ1, 3230 (NH) cmꢁ1. Anal.
Calcd. for C14H8F2N2O: C, 65.13; H, 3.10; N, 10.85%. Found: C, 65.34;
H, 3.39; N, 10.66%.
(1H, d, J ¼ 20 Hz, Ar–H), 7.40–7.51 (3H, m, Ar–H, 1H, t, J ¼ 10.64 Hz,
Ar–H, 1H, s, Ar–H (triazole)), 7.72–7.79 (1H, m, Ar–H), 7.88–7.95
(1H, d, J ¼ 20 Hz, Ar–H), 8.10–8.81 (1H, d, J ¼ 20 Hz, Ar–H), 8.51–
8.62 (1H, m, Ar–H); EIMS, m/z: 650 (Mþ þ 1); Anal. calcd. for
C25H16F13N5O: C, 46.19; H, 2.48; N, 10.78%. Found: C, 46.33; H, 2.56;
N, 10.90%.
6.2. Synthesis of 2-substituted-4-(prop-2-ynyloxy) quinazoline
(2a, 2b) and 2-substituted-3-(prop-2-ynyl) quinazolin-4(3H)-ones
(3a–c)
6.3.1.2. 2-Phenyl-4-((1-(3,3,4, 4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadeca-
fluorodecyl)-1H-1,2,3-triazol-4-yl)methoxy) quinazoline (4b). Yield:
0.158 g (47.0%); m.p. 128 ꢀC; IR (KBr, cmꢁ1): 1577 (C]N), 1497
6.2.1. General procedure
Quinazolin-4-one 1 (0.01 mol) was dissolved in acetone (15 ml),
K2CO3 (0.02 mol), NaI (5 mg) was added. Then, propargyl bromide
(0.015 mol) was slowly added drop wise over a period of 15 min at
room temperature. Reaction mixture was refluxed for 3–4 h and
solvent was removed under reduced pressure. The residue was
washed with n-hexane repeatedly to remove excess propargyl
bromide, added distilled water to remove excess potassium
carbonate and solid product separated was filtered, purified by
eluting through column using 2% ethyl acetate in n-hexane for
O-propargylated compound 2 and 8% ethyl acetate in n-hexane for
N-propargylated compound 3.
(C]C), 1239 (C–O–C); 1H NMR (300 MHz, CDCl3):
d 2.78–2.98 (2H,
m, CH2), 4.65–4.75 (2H, t, J ¼ 10.74 Hz, CH2), 5.85 (2H, s, OCH2),
7.42–7.55 (3H, m, Ar–H, 1H, t, J ¼ 6.2 Hz, Ar–H, 1H, s, Ar–H (tri-
azole)), 7.75–7.85 (1H, t, J ¼ 10.74 Hz, Ar–H), 7.95–8.00 (1H, d,
J ¼ 8.03 Hz, Ar–H), 8.13–8.20 (1H, d, J ¼ 8.0 Hz, Ar–H), 8.58–8.65
(2H, m, Ar–H); EIMS, m/z: 750 (Mþ þ 1); Anal. calcd. for
C27H16F17N5O: C, 43.27; H, 2.15; N, 9.35%. Found: C, 43.01; H, 2.05;
N, 9.18%.
6.3.1.3. 4-((1-(3,3,4, 4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl)-1H-1,2,3-
triazol-4-yl)methoxy)-2-(trifluoromethyl) quinazoline (4c). Yield:
0.244 g (84.77%); m.p. 93 ꢀC; IR (KBr, cmꢁ1): 1572 (C]N), 1499
6.2.1.1. 2-phenyl-4-(prop-2-ynyloxy) quinazoline (2a). Ref. [42].
(C]C), 1200 (C–O–C); 1H NMR (300 MHz, Acetone-d6):
d 2.80–2.83
(2H, m, CH2), 4.41–4.70 (2H, t, J ¼ 9.67 Hz, CH2), 5.44 (2H, s, OCH2),
7.31–7.62 (1H, m, Ar–H), 7.71 (1H, s, Ar–H), 7.62–7.81 (2H, d,
J ¼ 12.90 Hz Ar–H), 8.12–8.30 (1H, d, J ¼ 15 Hz, Ar–H); EIMS, m/z:
642 (Mþ þ 1); Anal. calcd. for C20H11F16N5O: C, 37.46; H, 1.73; N,
10.92%. Found: C, 37.30; H, 1.61; N, 10.77%.
6.2.1.2. 4-(prop-2-ynyl)-2-(trifluoromethyl) quinazolin-4-(3H)-one
(2b). Ref. [42].
6.2.1.3. 2-phenyl-3-(prop-2-ynyl) quinazolin-4(3H)-one (3a). Ref. [42].
6.2.1.4. 3-(prop-2-ynyl)-2-(trifluoromethyl) quinazolin-4-(3H)-one
(3b). Ref. [42].
6.3.1.4. 4-((1-(3,3,4, 4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorode
cyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-(trifluoro methyl) quinazoline
(4d). Yield: 0.286 g (85.91%); m.p. 105 ꢀC; IR (KBr, cmꢁ1): 1595
(C]N),1510 (C]C),1225 (C–O–C); 1H NMR (300 MHz, Acetone-d6):
6.2.1.5. 2-(2,6-difluorophenyl)-3-(prop-2-ynyl)
quinazolin-4(3H)-
one (3c). Yield: 2.55 g (86.25%); m.p. 133 ꢀC; IR (KBr, cmꢁ1): 1681
d
2.72–2.99 (2H, m, CH2), 4.50–4.80 (2H, t, J ¼ 10 Hz, CH2), 5.45 (2H,
(lactam CO), 1593 (C]N), 1472 (C]C); 1H NMR (200 MHz, DMSO-
s, OCH2), 7.41–7.72 (1H, m, Ar–H), 7.75 (1H, s, Ar–H), 7.64–7.85 (2H,
d, J ¼ 10 Hz, Ar–H), 8.18–8.39 (1H, d, J ¼ 15 Hz, Ar–H); EIMS, m/z:
742 (Mþ þ 1); Anal. calcd. for C22H11F20N5O: C, 35.64; H, 1.50; N,
9.45%. Found: C, 35.50; H, 1.39; N, 9.39%.
d6):
d 2.35–2.45 (1H, s, C^CH), 4.68–4.79 (2H, s, CH2), 7.10–7.25
(2H, m, Ar–H), 7.60–7.69 (3H, m, Ar–H), 7.79–7.89 (1H, m, Ar–H),
8.29–8.39 (1H, d, J ¼ 12.90 Hz, Ar–H); EIMS, m/z: 297 (Mþ þ 1);
Anal. calcd. for C17H10F2N2O: C, 68.92; H, 3.40; N, 9.46%. Found: C,
68.73; H, 3.32; N, 9.27%.
6.3.1.5. 2-Phenyl-4-((3-(3,3,4, 4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl)-
3H-1,2,3-triazol-4-yl)methoxy) quinazoline (5a). Yield: 0.117 g
(40.10%); m.p. 125 ꢀC; IR (KBr, cmꢁ1): 1566 (C]N), 1422 (C]C),
6.3. Synthesis of perfluoroalkyl-1H,1,2,3-triazol-4-yl substituted O-,
N-quinazolines (4a–d), (5a–b), (6a–f)
1239 (C–O–C); 1H NMR (300 MHz, Acetone-d6):
d 2.69–2.91 (2H, m,
CH2), 4.55–4.66 (2H, m, CH2), 5.79 (2H, s, OCH2), 7.15–7.21 (1H, d,
J ¼ 20 Hz, Ar–H), 7.37–7.48 (3H, m, Ar–H, 1H, t, J ¼ 10.24 Hz, Ar–H,
1H, s, Ar–H (triazole)), 7.60–7.79 (1H, m, Ar–H), 7.89–7.95 (1H, d,
J ¼ 20 Hz, Ar–H), 8.08–8.12 (1H, d, J ¼ 20 Hz, Ar–H), 8.50–8.60 (1H,
m, Ar–H); EIMS, m/z: 650 (Mþ þ 1); Anal. calcd. for C25H16F13N5O: C,
46.24; H, 2.48; N, 10.78%. Found: C, 46.02; H, 2.28; N, 10.59%.
6.3.1. General procedure
The propargylated quinazoline 2 or 3 (0.45 mmol) was dissolved
in dry THF and CuI (0.025 mmol) was added. Then, 10-azido-
1,1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8-heptadecafluorodecane/8-azido-1,1,1,
2,2,3,3,4,4,5,5,6,6,-trideca fluorooctane (0.45 mmol) in dry THF
was slowly added over a period of 30 min at room temperature
under nitrogen atmosphere and continued stirring overnight. The
solvent was removed under reduced pressure, the residue was
diluted with distilled water and extracted thrice with ethyl
acetate. The combined organic extract was dried over anhydrous
Na2SO4 and concentrated to get the product. The crude product
thus obtained was purified by column chromatography after its
adsorption onto silica gel (60/120) using 8% ethyl acetate in
hexane to separate O-isomer and 20% ethyl acetate in hexane to
separate N-isomer.
6.3.1.6. 2-Phenyl-4-((3-(3,3,4, 4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadeca
fluorodecyl)-3H-1,2,3-triazol-4-yl) methoxy) quinazoline (5b). Yield:
0.128 g (38.00%); m.p. 149 ꢀC; IR (KBr, cmꢁ1): 1577 (C]N), 1460
(C]C), 1210 (C–O–C); 1H NMR (300 MHz, CDCl3):
d 2.66–2.88 (2H,
m, CH2), 4.51–4.61 (2H, t, J ¼ 15 Hz, CH2), 5.89 (2H, s, OCH2), 7.38–
7.49 (4H, m, Ar–H), 7.68–7.79 (2H, m, Ar–H), 7.89–7.95 (1H, d,
J ¼ 20 Hz, Ar–H), 8.07–8.11 (1H, d, J ¼ 20 Hz, Ar–H), 8.50–8.60 (2H,
d, J ¼ 20 Hz, Ar–H); EIMS, m/z: 750 (Mþ þ 1); Anal. calcd. for
C27H16F17N5O: C, 43.27; H, 2.15; N, 9.35%. Found: C, 42.02; H, 2.03;
N, 9.02%.
6.3.1.1. 2-Phenyl-4-((1-(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl)-
1H-1,2,3-triazol-4-yl)methoxy) quinazoline (4a). Yield: 0.134 g
(46.0%); m.p. 118 ꢀC; IR (KBr, cmꢁ1): 1577 (C]N), 1422 (C]C), 1239
6.3.1.7. 2-Phenyl-3-((1-(3,3,4, 4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl)-
1H-1,2,3-triazol-4-yl)methyl) quinazolin-4(3H)-one (6a). Yield:
0.248 g (85.21%); m.p. 241 ꢀC; IR (KBr, cmꢁ1): 1678 (lactam CO),
(C–O–C); 1H NMR (300 MHz, Acetone-d6):
d
2.78–2.87 (2H, m, CH2),
4.68–4.78 (2H, t, J ¼ 10.74 Hz, CH2), 5.80 (2H, s, OCH2), 7.20–7.31
1606 (C]N), 1496 (C]C); 1H NMR (300 MHz, Acetone-d6):
d 2.85–

P. Mani Chandrika et al. / European Journal of Medicinal Chemistry 45 (2010) 78–84
83
3.00 (2H, m, CH2), 4.61–4.83 (2H, m, CH2), 5.25 (2H, s, NCH2), 7.40–
7.61 (4H, m, Ar–H), 7.57–7.78 (3H, m, Ar–H), 7.74–7.95 (1H, t,
J ¼ 10.34 Hz, Ar–H), 7.99 (1H, s, Ar–H), 8.13–8.41 (1H, m, Ar–H);
EIMS, m/z: 650 (Mþ þ 1); Anal. calcd. for C25H16F13N5O: C, 46.24; H,
2.48; N, 10.78%. Found: C, 46.09; H, 2.28; N, 10.60%.
Institute of Microbial Technology, Chandigarh. Cultures of test
organisms were maintained on Nutrient agar slants and were sub-
cultured in Petri dishes prior to testing. The media used was
Nutrient agar, Nutrient broth procured from Himedia Laboratories,
Mumbai. The minimum inhibitory concentration was determined
by broth dilution method [46].
6.3.1.8. 2-Phenyl-3-((1-(3,3,4, 4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptade-
cafluorodecyl)-1H-1,2,3-triazol-4-yl)methyl) quinazolin-4(3H)-one
(6b). Yield: 0.297 g (88.12%); m.p. 160 ꢀC; IR (KBr, cmꢁ1): 1677
(lactam CO), 1585 (C]N), 1473 (C]C); 1H NMR (200 MHz, DMSO-
6.4.2. Antifungal activity: procedure
Antifungal activity is studied by agar cup diffusion method [46].
The readymade potato dextrose agar (PDA) medium (Himedia,
39 g) was suspended in distilled water (1000 ml) and heated to
boiling until it dissolved completely. The medium and Petri dishes
were autoclaved at pressure of 15 lb/inch for 20 min. Agar cup
bioassay was employed for testing antifungal activity. The medium
was poured into sterile Petri dishes under aseptic conditions in
a laminar flow chamber. When the medium in the plates solidified,
0.5 ml of (week old) culture of test organism was inoculated and
uniformly spread over the agar surface with a sterile L-shaped rod.
Solutions were prepared by dissolving the compound in acetone
d6):
d
2.61–2.81 (2H, m, CH2), 4.61–4.80 (2H, t, J ¼ 10 Hz, CH2), 5.19
(2H, s, NCH2), 7.47–7.66 (6H, m, Ar–H), 7.63–7.77 (1H, d,
J ¼ 13.34 Hz, Ar–H), 7.78–7.97 (1H, t, J ¼ 10 Hz, Ar–H), 8.15–8.30
(2H, d, J ¼ 20 Hz, Ar–H); EIMS, m/z: 750 (Mþ þ 1); Anal. calcd. for
C27H16F17N5O: C, 43.27; H, 2.15; N, 9.35%. Found: C, 43.01; H, 2.08;
N, 9.26%.
6.3.1.9. 2-(2,6-difluorophenyl)-3-((1-(3,3,4, 4,5,5,6,6,7,7,8,8,8-tride-
cafluorooctyl)-1H-1,2,3-triazol-4-yl)methyl)
quinazolin-4(3H)-one
(6c). Yield: 0.256 g (83.20%); m.p. 144.0 ꢀC; IR (KBr, cmꢁ1): 1676
and different concentrations (30
mg/ml, 100 mg/ml) were made.
After inoculation, cups were scooped out with 6 mm sterile cork
borer and the lids of the dishes were replaced. To each cup, different
(lactam CO),1596 (C]N), 1471 (C]C); 1H NMR (200 MHz, Acetone-
d6):
d
2.80–3.00 (2H, m, CH2), 4.65–4.76 (2H, t, J ¼ 9.67 Hz, CH2),
5.19 (2H, s, NCH2), 7.10–7.20 (2H, t, J ¼ 12.90 Hz, Ar–H), 7.51–7.70
(3H, m, Ar–H), 7.75–7.84 (1H, d, J ¼ 12.90 Hz, Ar–H), 7.90 (1H, s, Ar–
H), 8.20–8.30 (1H, d, J ¼ 12.90 Hz, Ar–H); EIMS, m/z: 686 (Mþ þ 1);
Anal. calcd. for C25H14F15N5O: C, 43.81; H, 2.06; N, 10.22%. Found: C,
43.65; H, 1.94; N, 10.08%.
concentrations (30
Controls were maintained with acetone and amphotericin-B
(50
g/ml). The treated and the controls were kept at 28 ꢀC for 48 h.
mg/ml, 100 mg/ml) of test solutions were added.
m
Inhibition zones were measured and the diameter was calculated in
millimeter.
6.3.1.10. 2-(2,6-difluorophenyl)-3-((1-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,
10-heptadecafluorodecyl)-1H-1,2,3-triazol-4-yl)methyl) quinazolin-
4(3H)-one (6d). Yield: 0.305 g (86.50%); m.p. 156.0 ꢀC; IR
(KBr,cmꢁ1): 1675 (lactam CO), 1595 (C]N), 1472 (C]C); 1H NMR
Acknowledgements
Authors are thankful to the Principal, Dr. G. Achaiah, University
College of Pharmaceutical Sciences, Kakatiya University, Dr. J.S.
Yadav, Director, I.I.C.T., Hyderabad, Shri S. Narayan Reddy, Head,
Fluoroorganic Division, and I.I.C.T. for their constant encourage-
ment and facilities. One of the authors (P.M.C.) is grateful to
A.I.C.T.E., New Delhi for the grant of research fellowship under
Quality Improvement Programme (Q.I.P.)
(300 MHz, Acetone-d6):
d 2.90–3.00 (2H, m, CH2), 4.74–4.85 (2H, t,
J ¼ 9.67 Hz, CH2), 5.28 (2H, s, NCH2), 7.15–7.24 (2H, m, Ar–H), 7.50–
7.61 (1H, m, Ar–H), 7.65–7.74 (3H, m, Ar–H), 7.94–8.10 (1H, d,
J ¼ 10 Hz, Ar–H), 8.28–8.37 (1H, m, Ar–H); EIMS, m/z: 786 (Mþ þ 1);
Anal. calcd. for C27H14F19N5O: C, 41.29; H, 1.80; N, 8.92%. Found: C,
41.35; H, 1.92; N, 9.01%.
References
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0.234 g (81.15%); m.p. 99 ꢀC; IR (KBr, cmꢁ1): 1695 (lactam CO), 1612
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d 2.95–3.04
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