Synthesis, cytotoxicity by bioluminescence inhibition, antibacterial and antifungal activity of ([1,2,4]triazolo[1,5-c]quinazolin-2-ylthio)carboxylic acid amides

Article abstract of DOI:10.1002/ardp.200900077

We report in this work the synthesis, cytotoxicity, and antimicrobial activity of ([1,2,4]triazolo[1,5-c]quinazolin-2-ylthio)carboxylic acid amides 4-7 in connection with our previous research in the preparation of triazoloquinazoline derivatives. Due to

Full text of DOI:10.1002/ardp.200900077

Arch. Pharm. Chem. Life Sci. 2009, 342, 651–662
L. N. Antipenko et al.
651
Full Paper
Synthesis, Cytotoxicity by Bioluminescence Inhibition,
Antibacterial and Antifungal Activity of ([1,2,4]Triazolo[1,5-
c]quinazolin-2-ylthio)carboxylic Acid Amides
Lyudmila N. Antipenko1, Alexander V. Karpenko1, Sergey I. Kovalenko1, Andrew M. Katsev2,
Elena Z. Komarovska-Porokhnyavets3, and Vladimir P. Novikov3
1 Department of Pharmaceutical Chemistry, Zaporozhye State Medical University, Zaporozhye, Ukraine
2 Department of Pharmacy, Crimea State Medical University, Simferopol, Ukraine
3 Department of Technology of Biological Active Substances, Pharmacy and Biotechnology, National
University “Lviv Polytechnic”, Lviv, Ukraine
We report in this work the synthesis, cytotoxicity, and antimicrobial activity of ([1,2,4]tri-
azolo[1,5-c]quinazolin-2-ylthio)carboxylic acid amides 4–7 in connection with our previous
research in the preparation of triazoloquinazoline derivatives. Due to simplicity, general avail-
ability of starting materials, and high yields, the most reliable method of synthesis appeared to
be the one with N,N-carbonyldiimidazole activation stage. The chemical structures of all
1
obtained substances were deduced from FT-IR, H-NMR, EI-MS, and LC-MS spectral data. The
results of cytotoxicity evaluated by bioluminescence inhibition of bacterium Photobacterium
leiognathi, strain Sh1 showed that compounds 4.1, 4.6, and 6.1 were the most cytotoxic. Investiga-
tion of the antimicrobial and antifungal activity of amides 4–7 (concentration 5 mg/mL) was car-
ried out by the stiff-plate agar-diffusion method. We found that the compounds possessed low
(4.1, 4.7) antifungal activity against Candida tenuis and strong (4.21, 5.1, 5.9) or inefficient (4.7,
4.12, 4.16) activity against Aspergillus niger. Substances 5.1 and 5.9 slightly affected Mycobacterium
luteum. Staphylococcus aureus was resistant to all obtained substances, and only the n-butyramide
derivatives 7.1 and 7.5 inhibited the growth of Escherichia coli. Hence, there was no strong corre-
lation between bioluminescence inhibition and antimicrobial activity of the investigated sub-
stances.
Keywords: Antifungal / Antibacterial / Bioluminescence / Cytotoxicity / 2-Thio-[1,2,4]triazolo[1,5-c]quinazoline /
Received: April 9, 2009; Accepted: July 22, 2009
DOI 10.1002/ardp.200900077
known as fireflies) and a few species of bacteria (Photobac-
terium phosphoreum, P. leiognathi, Vibrio fischeri, V. harveyi)
possess the ability to emit light [2]. The biochemistry and
genetics of the light reaction (luciferin oxidation) have
been widely studied, and now scientists are exploring
other potential applications of luminescence in micro-
bial quality control of soil, air, food products, and drink-
ing water. Consequently, bioluminescence (BL) inhibi-
tion test is a simple rapid in-vitro method for the screen-
ing and monitoring of a wide range of organic xenobiot-
ics [2]. Still, it should always be kept in mind that rigor-
ous testing of the method should be carried out in com-
parison to accepted methods.
Introduction
Nowadays, biotesting, a determination of e.g., toxicity, by
direct action on a living organism, is widely used as con-
trol of the biological system state on different levels of an
ecosystem [1]. It is known that certain insects (e.g., beetles
Correspondence: Lyudmila N. Antipenko, Department of Pharmaceuti-
cal Chemistry, Zaporozhye State Medical University; 26, Mayakovsky
ave., 69035, Zaporozhye, Ukraine.
E-mail: antypenko.l@gmail.com
Fax: +38 061 234-15-71
Abbreviation: bioluminescence (BL)
i 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

652
L. N. Antipenko et al.
Arch. Pharm. Chem. Life Sci. 2009, 342, 651–662
Figure 1. Chemical structures of the antifungals – 1,2,4-triazole derivatives.
Figure 2. Chemical structures of the [1,2,4]triazolo[1,5-c]quinazoline derivatives with antimicrobial properties.
At the present time, medicine is faced with the real mentioned core formed [1,2,4]triazolo[1,5-c]quinazolin-2-
and frightening threat of entering the “postantibiotic thiones B, which also demonstrated antibacterial activity
era”, when existing antibiotic arsenal will become [9–12]. Moreover, in our previous research it was proved
largely ineffective against bacterial and fungal infections that ([1,2,4]triazolo[1,5-c]quinazolin-2-ylthio)acetic and
because of the accumulation of antibiotic resistance -3-propionic acids C possess strong antifungal activity
mechanisms: selection of mutants which produce modi- against C. albicans [13].
fied low-affinity drug targets, acquirement of mobile
Consequently, it appeared to be interesting and useful
genetic determinants of drug-inactivating enzymes, tar- to continue investigations in the field of 2-thio-[1,2,4]tri-
get protection and bypass system [3, 4]. The usage of azolo[1,5-c]quinazoline derivatives. The aim of this work
broad-spectrum antibiotics increases the risk of thera- was to estimate the cytotoxicity of novel ([1,2,4]tri-
peutic failure, drug side effects and excess costs of care. azolo[1,5-c]quinazolin-2-ylthio)carboxylic acid amides by
Confronting this danger effectively requires new strat- measuring the light extinction of luminescent bacteria,
egies to be implemented across the healthcare such as and to evaluate their antimicrobial and antifungal prop-
synthesis of new, more selective and effective antimicro- erties.
bial and antifungal substances.
More than that, 1,2,4-triazole derivatives are well
known to be effective antifungal drugs [5]. Thus, second
generation derivatives of fluconazol – voriconazol and
Results and discussion
ravuconazol – (Fig. 1), showed better in-vitro activity Chemistry
against Aspergillus spp., Candida spp., Fusarium spp., and The above-mentioned amides 4–7 were synthesized in
Scedosporium ariospermum in comparison with the refer- several ways. Since the synthesis from esters usually
ence antimycotics [6]. Another derivative of itraconazol – works well, we started from ammonolysis of methyl ester
albaconazol (Fig. 1), which contains 1,2,4-triazole and 2 (Scheme 1). The latter was obtained by a reported proce-
quinazoline rings in its structure, is in early Phase of clin- dure from the potassium salt 1 [13], yet, the resulting
ical development and shows very potent activity against ([1,2,4]triazolo[1,5-c]quinazolin-2-ylthio)acetic acid amide
species of Candida, Cryptococcus and Aspergillus [7].
Fusion of the 1,2,4-triazole ring to quinazoline leads to
4.1 turned out to be contaminated with side products.
The attempt to conduct aminolysis of ester 2 by treat-
formation of new antimicrobial N-aryl-(4-[1,2,4]tri- ment with benzylamine at 808C in DMF lead to degrada-
azolo[1,5-c]quinazolin-2-yl-thiazol-2-yl)acetamides tion products instead of the anticipated amide 4.5
A
(Fig. 2) [8]. Introduction of a sulphur atom in the above- (Scheme 1, Table 1).
i 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2009, 342, 651–662
2-Thio-[1,2,4]triazolo[1,5-c]quinazolines
653
Reactions and conditions: (a) Propan-2-ol, r.t., 48 h; (b) propan-2-ol / H2O, reflux, 2 h; (c) propan-2-ol, reflux, 2 h; (d) i) CDI,
dioxane, 60–808C, ii) amine, reflux, 1 h.
Scheme 1. Synthesis of the compounds 4–7.
Taking into account the low electrophilicity of carb-
The structures of all synthesized compounds were con-
oxylic group of ester 2, we developed several alternative firmed by their spectral data. Thus, the position of the car-
methods for the target compound preparation. The bonyl absorbtion band in FT-IR spectra was influenced by
amides 4.1, 4.6, 4.9, 4.12, 4.14, 4.15, 4.20, 5.4, 5.6, 5.9–5.12, the physical state of the compounds as substances were
6.1, 6.2, and 7.1–7.7 were obtained as the result of alkyla- taken in solid state. Hence, primary amides showed ms and
tion of the potassium salt 1 by halogenoacylamides masNH vibration at 3026 and 2968 cm–1. Free NH-stretching
under reflux in propan-2-ol (Scheme 1). Changing the vibration of secondary amides was observed as multiple
reaction conditions by adding water did not greatly bands in the 3347 to 3042 cm–1 region. Primary amides
affect the yield of the products. However, the use of the have a strong «Amide I» (mC=O) band at 1686 cm–1. The latter
given method was limited by the application of commer- band appeared near 1683–1638 cm–1 in the case of open
cially inaccessible halogenoacylamides, which were syn- chain secondary amides, and shifted to the 1697–
thesized through acylation of the corresponding amines 1651 cm–1 region for aryl amides because of the ring influ-
according to the general procedure [14].
ence on the non-bondened electron pair of the nitrogen.
Our subsequent efforts were directed towards the The carbonyl frequency of tertiary amides occurred in the
development of one more efficient method of synthesis. range of 1649–1634 cm–1. The «Amide II» band (mC-N and
We used N,N-carbonyldiimidazole for the activation of dN-H) was shown as sharp absorption band near 1623 cm–1
the carboxylic group of acids 3.1–3.3 with subsequent for the primary amide, in the region 1558 to 1537 cm–1 for
aminolysis of the resulting intermediates. The advan- acyclic amides, and 1590–1535 cm–1 for aryl amides. The
tages of this reaction were purity and high yields of the second weaker band near 1274–1240 cm–1 also resulted
products 4.2–4.5, 4.7–4.11, 4.13, 4.16–4.19, 4.21, 5.1–5.3, from interaction between NH-bending and CH-stretching
and 5.5–5.8 (Scheme 1).
vibrations. The medium bands in the 796–610 cm–1 region
i 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

654
L. N. Antipenko et al.
Arch. Pharm. Chem. Life Sci. 2009, 342, 651–662
Table 1. Physical data of ([1,2,4]triazolo[1,5-c]quinazolin-2-ylthio)carboxylic acid amides 4–7.
Compd.
n
R
R1
R2
R3
Yield (%)
(method)
Recryst.
Solvent*
M.p.
(8C)
50.0 (A)
70.7 (B)
57.0 (D)
33.3 (D)
22.1 (D)
62.5 (D)
34.3 (C)
73.2 (D)
51.5 (D)
50.6 (B)
53.2 (D)
42.3 (D)
43.1 (D)
36.7 (B)
32.5 (D)
39.5 (C)
21.0 (B)
29.9 (D)
47.0(D)
22.2(D)
40.0 (D)
54.5 (C)
57.0 (D)
96.1 (D)
69.0 (D)
61.8 (D)
31.9 (C)
15.6 (D)
34.3 (C)
30.6 (D)
68.9 (D)
42.9 (C)
25.4 (C)
62.5 (C)
58.4 (C)
30.0 (C)
36.7 (C)
41.1 (C)
17.0 (C)
21.0 (C)
21.8 (C)
34.0 (C)
36.2 (C)
46.4 (C)
4.1
0
H
H
H
–
§
250–252
4.2
4.3
4.4
4.5
4.6
4.7
4.8
0
0
0
0
0
0
0
H
H
H
H
H
H
H
H
H
H
H
H
Bu
–
–
–
–
–
–
–
p
156–158
203–205
180–182
207–209
158–160
156–158
230–232
cyclopropyl
C(CH3)3
Bn
#
#
–
–
#
§
CH2-COOEt
-(CH2)5-
–(CH2)2O(CH2)2-
4.9
0
H
–
–
H
#
196–198
4.10
4.11
4.12
4.13
4.14
4.15
4.16
4.17
4.18
4.19
4.20
4.21
5.1
5.2
5.3
5.4
5.5
5.6
5.7
5.8
5.9
5.10
5.11
5.12
6.1
6.2
7.1
7.2
7.3
7.4
7.5
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1
1
2
2
2
2
2
2
2
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
H
H
H
H
H
H
H
H
–
–
–
–
–
–
–
–
-
–
–
–
–
–
–
–
–
-
2-Me
3-Me
2-OMe
2-Me-4-Cl
2-NO2
4-NO2
3-Cl
4-Cl
4-Br
3-CF3
4-COOEt
–
–
–
–
–
-
H
2-Me
3-Me
2-OMe
4-NO2
4-Cl
3-CF3
–
3-Me
–
H
2-Me
2-OMe
2-OMe-4-Cl
4-Br
3-CF3
#
#
#
#
#
#
#
#
#
p
#
–
p
–
#
p
166–168
162–168
174–176
224–226
158–160
221–223
154–156
208–210
228–230
142–144
178–180
138–140
122–124
126–128
164–166
164–166
169–171
172–174
169–171
142–144
118–120
230–232
202–204
176–178
124–126
178–180
196–198
184–186
186–188
140–142
156–158
212–124
142–144
-
-
H
Et
H
H
H
Et
Bu
C(CH3)3
Bn
-(CH2)5-
-(CH2)2O(CH2)2-
p
H
H
H
H
H
H
H
–
–
–
–
–
–
–
#
#
#
p
#
#
p
-(CH2)2O(CH2)2-
§
§
H
H
–
–
–
–
–
–
–
Bn
–
–
–
–
–
–
#
#
#
#
#
#
p
7.6
7.7
§ dioxane; # propan-2-ol / dioxane (2 : 1); p propan-2-ol.
appeared due to out-of-plane NH wagging. Also, FT-IR spec- showed up as two inequivalent one-proton singlets at
tra showed frequencies of certain molecular vibration in 7.72 and 7.28 ppm, as a result of its hindered rotation
terms of single bonds of 1,2,4-triazoloquinazoline, which around the anisotropic C=O group. For (aryl)alkyl amides,
own specific absorbtion influenced the intensity and fre- broadened one-proton triplet (for 4.2, 4.5, 4.6, 5.1, 5.3, 7.1)
quency ofone another.
or a singlet (for 4.3, 5.2) of the amide group were observed
In the 1H-NMR spectra, the [1,2,4]triazolo[1,5-c]quinazo- in the low field (8.84–8.00 ppm). One-proton NH broad-
line system was characterized by signals in the aromatic ened singlet of the arylamides 4.9–4.20, 5.6–5.12, 6.2, 7.2–
area (8.43–7.76 ppm) and a characteristic H-5 singlet at 7.7 shifted more to the low field (11.05–9.12 ppm). It is
9.54–9.48 ppm, in agreement with the literature data also interesting to notice that two-proton singlet of the
[13, 15]. The protons of the amide group of compound 4.1 SCH2 group of acetic acid amides 4.2–4.4 resonated at
i 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2009, 342, 651–662
2-Thio-[1,2,4]triazolo[1,5-c]quinazolines
655
Table 2. Values of BL in acute action test (%).
4.05–4.02 ppm, and protons of the SCH-group of a-pro-
pionic acid derivatives 5.1–5.12 appeared in the lower
area of spectrum (5.05–4.56 ppm) as quadruplet. The lat-
ter group-triplet signal shifted upfield for b-propionic
acid amides 6.1, 6.2 (3.53 ppm) and for n-butyric acid
amides 7.2–7.7 (3.38–3.32 ppm).
Compound*
Concentration (mg/mL)
0
0.025
0.1
0.25
4.1
4.2
4.4
4.5
4.6
4.7
4.8
4.9
4.10
4.11
4.12
4.13
4.14
4.15
4.16
4.17
4.18
4.19
4.20
4.21
5.1
5.2
5.3
5.4
5.5
5.6
5.7
5.8
5.9
5.10
5.11
5.12
6.1
6.2
7.1
7.2
7.3
7.4
7.5
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
58.1
39.1
44.1
71.7
46.9
26.0
90.4
69.4
61.8
26.5
15.6
46.9
6.6
84.8
16.3
99.2
70.3
74.4
12.4
68.8
57.2
105.9
98.4
78.3
149.0
67.8
77.2
99.3
34.7
110.4
75.7
71.4
35.7
66.7
116.2
97.5
97.5
82.0
60.7
98.4
82.0
80.7
141.7
74.4
39.1
39.7
47.8
39.8
8.7
82.7
91.7
44.1
33.1
26.0
65.6
8.8
80.9
10.2
99.2
70.3
119.0
17.4
79.2
43.4
94.9
89.1
52.2
122.4
62.6
99.3
99.3
116.2
177.1
75.7
83.3
19.0
83.3
76.3
82.8
82.8
77.3
65.9
82.0
89.1
9.1
130.2
26.1
22.1
38.2
23.4
5.2
LC-MS confirmed the purity of obtained substances 4–7
and demonstrated their appropriately protonated molec-
ular ions [M + H]+. The EI-MS spectra of acetic acid deriv-
atives (4.1, 4.6, 4.17, 4.21) were characterized by succes-
sive fragmentation of the substances. Thus, during the
cleavage ions [HetarylSCH2CO]+ (m/z: 243), [HetarylSCH2]+
(m/z: 215), [HetarylSH]+ (m/z: 202) were formed through
the appropriate split-off of the CH2 fragments and the
amide and acyl moiety. A similar cleavage took place for
substances 5.2, 5.4, 5.12 with proper detection of the ions
peaks with m/z: 257, 230, 202. The base peaks corre-
sponded to the ion [HetarylSCH-CH3]+ (m/z: 229) for com-
pounds 5.2, 5.12 and [HetarylSCH2CH2]+ for n-butyric acid
derivatives (7.1, 7.6). Above mentioned data were in
accordance with literature reports for this heterocyclic
system [13, 15].
76.9
99.2
59.6
44.1
34.7
82.0
11.0
71.7
100.0
106.6
82.0
131.4
24.8
83.3
31.2
77.2
98.4
19.6
100.0
65.2
99.3
105.9
104.0
100.0
78.3
95.2
11.9
95.2
78.0
110.4
110.4
82.0
57.2
93.8
89.1
0
Pharmacology
The pharmacological investigations started from the esti-
mation of cytoxicity of the novel ([1,2,4]triazolo[1,5-c]qui-
nazolin-2-ylthio)carboxylic acids by measuring the inhib-
ition of BL of Photobacterium leiognathi in acute (inhibit-
ing BL, Table 2) and chronic action tests (inhibiting BL
and growth, Table 3).
Thus, in the acute action test the strongest inhibition
of BL was observed in the samples treated mostly with
amides of acetic and less with those of 2-propionic acid
(4.2, 4.4, 4.6, 4.7, 4.11, 4.14, 4.20, 5.1, 5.6, 6.1). A moderate
action was shown by almost 25% of all substances (4.5,
4.8–4.10, 4.13, 4.15, 4.18, 4.21, 5.2, 5.4, 5.6, 5.11, 5.12, 6.2,
7.1, 7.4, 7.5, 7.7). Some of the obtained compounds
revealed an inhibition effect only in concentrations of
0.025 and 0.1 mg/mL (4.1, 4.16, 5.7, 5.9). It is remarkable
that substances 4.19 and 5.10 were BL promoters.
It was established that opposite to the previous test,
where substances did or did not inhibit BL, in chronic
7.6
7.7
Tetracyclin
DMSO (control) 100.0
119.6
110.4
* substance 4.3 was not tested.
action test, substances either inhibited or potentiated BL were the most toxic compounds among all investigated.
(Table 3). Hence, amides 4.1, 4.6, 4.16, 6.1, and 7.7 have It is worth mentioning that amides 4.1, 4.16, 5.7, 5.9 (in
shown strong cytotoxic activity, and 4.7, 4.12, 4.18, 4.13, the acute test) and 5.1, 5.12, 6.2 (in chronic test) inhibited
5.10, 5.5, 5.9, 7.2, 7.4, 7.5, 7.6 show a moderate inhibitory BL or bacterial growth only in the first two concentra-
effect, compared to the standard. All other compounds tions (0.025 and 0.1 mg/mL), demonstrating the hormesis
promoted BL. Among the latter, substances 4.4, 4.5, 4.15 phenomenon of low-dose inhibition [16].
were cytotoxic only in concentration 0.25 mg/mL.
The results of the antimicrobial assay showed that
Summing up the BL assay results, substances have 4.1, some of synthesized substances (4.1, 4.7, 4.12, 4.16, 4.21,
4.6, 6.1 strongly, and 4.13, 4.18, 7.4, 7.5 moderately inhib- 5.1, 5.9, 5.12) posessed antifungal activity against Aspergil-
ited both BL and the growth of bacteria, namely, they lus niger, comparable with nystatine activity, but had no
i 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

656
L. N. Antipenko et al.
Arch. Pharm. Chem. Life Sci. 2009, 342, 651–662
Table 3. Values of BL in chronic action test (%).
growth of Mycobacterium luteum. The n-butyric acid deriv-
atives 7.1 and 7.5 demonstrated antimicrobial activity
against Escherichia coli. The mentioned compounds 4.12,
5.9 and 7.5 had a 2-methoxy-phenyl substituent, 4.16 and
7.5 a chlorine.
Compound*
Concentration (mg/mL)
0
0.025
0.1
0.25
4.1
100.0
190.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
36.8
14.7
5.9
In conclusion, 42 novel compounds, namely ([1,2,4]tri-
azolo[1,5-c]quinazolin-2-ylthio)carboxylic acid amides
were synthesized and evaluated for their cytotoxicity,
antibacterial, and antimicrobial activity. Comparing the
results of antimicrobial screening with bioluminescence
tests, it was found that the compounds that didn't inhibit
BL and growth of bacteria at all, appeared to have no anti-
bacterial properties. The most active substances in the
entire series appeared to be the derivatives of acetic acid,
4.1 and 4.7 against Candida tenuis, of n-butyric acid, 7.1
and 7.5 against Escherichia coli, and of 2-propionic and ace-
tic acid, 5.1 and 5.9, and 4.21, respectively against Asper-
gillus niger. Almost all substances, except 4.21 and 7.1,
that were shown to be antimicotics or antifungals, were
cytotoxic for bioluminescent bacteria. In spite of this
fact, there was no strong correlation between BL inhibi-
tion and antimicrobial activity of the investigated sub-
stances.
4.2
4.4
4.5
4.6
4.7
4.8
4.9
4.10
4.11
4.12
4.13
4.14
4.15
4.16
4.17
4.18
4.19
4.20
4.21
5.1
5.2
5.3
5.4
5.5
5.6
5.7
5.8
5.9
5.10
5.11
5.12
6.1
6.2
7.1
7.2
7.3
7.4
7.5
268.1
200.0
135.0
35.3
383.0
216.7
120.0
31.8
105.0
228.1
180.5
183.3
200.0
82.5
287.2
50.0
82.5
8.8
67.5
82.5
175.4
180.5
250.0
200.0
60.0
70.6
133.3
25.5
0.0
263.2
315.8
183.3
266.7
67.5
97.1
97.1
166.7
255.3
56.3
106.0
70.6
103.8
45.1
265.6
55.6
166.7
105.9
191.5
83.3
191.5
183.3
116.7
45.0
76.9
95.7
44.1
51.5
44.1
93.8
85.1
74.5
166.7
127.7
0.0
157.9
88.2
191.7
101.5
250.0
55.6
233.3
105.9
223.4
58.3
255.3
250.0
116.7
82.5
76.9
140.4
7.4
14.7
5.9
104.2
85.1
85.1
61.8
83.3
79.4
52.9
338.3
70.6
315.8
157.9
125.0
111.1
116.7
105.9
255.3
25.0
255.3
133.3
133.3
37.5
96.2
300.0
88.2
44.1
80.9
97.9
117.0
12.8
61.8
62.5
52.9
52.9
0
Experimental
Chemistry
Melting points were determined in open capillary tubes and
were uncorrected. IR spectra (4000–600 cm–1) were recorded on a
Bruker ALPHA FT-IR spectrometer (Bruker Bioscience, USA) using
1
a module for measuring attenuated total reflection (ATR). H-
NMR spectra (400 MHz and 500 MHz) were recorded on a Varian-
Mercury 400 (Varian Inc., Palo Alto, CA, USA) and Bruker Avance
DRX-500 spectrometers with TMS as internal standard in DMSO-
d6 solution. LC-MS were recorded using chromatography / mass
spectrometric system which consists of high performance liquid
chromatograph “Agilent 1100 Series” (Agilent, Palo Alto, CA,
USA) equipped with diode-matrix and mass-selective detector
“Agilent LC/MSD SL” (atmospheric pressure chemical ionization
– APCI). Electron impact mass spectra (EI-MS) were recorded on a
Varian 1200 L instrument at 70 eV (Varian). The purity of all
obtained compounds was checked by 1H-NMR and LC-MS.
Substances 1–3 were synthesized according to the reported
procedures [13, 15]. Other starting materials and solvents were
obtained from commercially available sources and used without
additional purification.
35.3
52.1
88.2
35.3
0
74.5
7.6
7.7
Tetracyclin
0
DMSO (control) 100.0
127.7
127.7
* Compound 4.3 was not tested.
antibacterial activity against Staphylococcus aureus
(Table 4).
The structure / activity study showed that antimicro-
bial activity was dependent on the nature of the substitu-
ents. Considering 2-propionamide ones 5.1 and 5.9, they
were more active against Aspergillus niger compared to
the acetamide derivatives 4.7, 4.12, 4.16, exept for 4.21.
The growth of Candida tenuis was non-sensitive to almost
all investigated compounds, beside the aliphatic-substi-
tuted acetamides 4.1 and 4.7. Only two N-phenyl-substi-
tuted propionamides 5.9, 5.12 slightly inhibited the
General procedure for synthesis of ([1,2,4]triazolo[1,5-c]-
quinazolin-2-ylthio)carboxylic acid amides 4–7 (Table 1)
Method A: 25% Ammonia solution (10 mL) was added to a sus-
pension of 2 (1.05 g, 3.8 mmol) in 2-propanol (5 mL). The mixture
was left at room temperature for 48 h. The precipitate was fil-
tered out, washed with water, recrystallized from suitable sol-
vent, and dried.
Method B: A solution of the proper halogenoacylanilide
(6 mmol) in 2-propanol (10 mL) was added to a solution of 1
i 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2009, 342, 651–662
2-Thio-[1,2,4]triazolo[1,5-c]quinazolines
657
Table 4. Inhibitory zones of the investigated compounds (mm).
Compound*
Concentration
(mg/mL)
Escherichia
coli
Staphylococcus Mycobacterium Candida
Aspergillus
niger
aureus
luteum
tenuis
4.1
4.7
4.12
4.16
4.21
5.1
5.9
5.12
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
0.1
0.1
0.1
–
–
–
–
–
–
–
–
13
14
16
0
–
–
–
–
–
–
–
–
–
–
18
11
21
–
–
–
–
–
–
11
14
–
14
15
–
–
–
–
–
–
–
–
–
24
–
–
16
15
11
25
25
25
–
–
–
–
25
–
7.1
7.5
–
Vancomicin
Nystatin
Oxacillin
58
15
–
0
* Bacteria were resistant to all other tested compounds.
(1.2 g, 5 mmol) in H2O (10 mL). The mixture was refluxed for
2 hours and then cooled to room temperature. Water was added
to the resulting mixture. The precipitate was filtered out,
washed with water, recrystallized from suitable solvent, and
dried.
Method C: The proper halogenoacylamide (6 mmol) was
added to a suspension of 1 (1.2 g, 5 mmol) in 2-propanol (10 mL).
Further work-up as in method B afforded the proper substances.
Method D: Carbonyldiimidazole (1.0 g, 6 mmol) was added to
a solution of the acid 3.1, 3.2, or 3.3 (5 mmol) in anhydrous diox-
ane (15 mL). The resulting mixture was heated at 60–808C until
CO2 evolution stopped. The corresponding amine (6 mmol) was
added, refluxed for 1 hour, and then cooled to room tempera-
ture. Further work-up as in method B afforded the proper sub-
stances.
Compound 4.3
IR (cm–1): 3305, 3083, 3009, 1651, 1620, 1535, 1511, 1478, 1392,
1325, 1266, 1198, 1104, 1000, 902, 766, 714, 669; 1H-NMR
(400 MHz) d: 9.49 (s, 1H, H-5), 8.38 (d, J = 7.8 Hz, 1H, H-10), 8.05 (d,
J = 7.8 Hz, 1H, H-7), 7.93 (m, 2H, H-8, NH), 7.82 (t, J = 7.6 Hz, 1H, H-
9), 4.03 (s, 2H, SCH2), 1.26 (s, 9H, (CH3)3); LC-MS m/z: 300 [M + H]+.
Anal. calcd. for C15H17N5OS: C, 57.12; H, 5.43; N, 22.20; S, 10.17.
Found: C, 57.07; H, 5.49; N, 22.28; S, 10.13.
Compound 4.4
IR (cm–1): 3296, 3069, 2957, 2972, 2864, 1666, 1622, 1555, 1513,
1477, 1452, 1379, 1358, 1306, 1253, 1223, 1145, 1106, 898, 762,
717, 648; 1H-NMR (400 MHz) d: 9.48 (s, 1H, H-5), 8.78 (t, J = 8.0 Hz,
1H, NH), 8.37 (d, J = 8.0 Hz, 1H, H-10), 8.06 (d, J = 8.0 Hz, 1H, H-7),
7.94 (t, J = 7.8 Hz, 1H, H-8), 7.82 (t, J = 7.8 Hz, 1H, H-9), 7.21 (m, 5H,
Ph), 4.32 (d, J = 6.2 Hz, 2H, NCH2), 4.14 (c, 2H, SCH2); LC-MS m/z:
316 [M + H]+. Anal. calcd. for C15H17N5OS: C, 57.12; H, 5.43; N,
22.20; S, 10.17. Found: C, 57.07; H, 5.49; N, 22.28; S, 10.13.
Compound 4.1
IR (cm–1): 3026, 2968, 1686, 1646, 1623, 1597, 1520, 1471, 1443,
1410, 1360, 1252, 1189, 1133, 1101, 1026, 968, 898, 820, 774,
739, 706, 622; 1H-NMR (400 MHz) d: 9.52 (s, 1H, H-5), 8.40 (d, J =
8.0 Hz, 1H, H-10), 8.06 (d, J = 8.0 Hz, 1H, H-7), 7.95 (t, J = 8.0 Hz,
1H, H-8), 7.83 (t, J = 8.0 Hz, 1H, H-9), 7.72 (br.s, 2H, NH2), 4.36 (t, J =
4.9 Hz, 2H, SCH2); LC-MS m/z: 260 [M + H]+, 262; EI-MS m/z (I,%):
260 (3.0), 259 (10.7) [M + 1]+, 242 (5.3), 218 (4.7), 217 (10.4), 216
(100.0), 215 (55.4), 202 (9.2), 188 (8.2), 187 (11.0), 184 (4.7), 171
(8.0), 129 (18.7), 102 (5.8), 62 (4.7), 58 (11.1). Anal. calcd. for
C11H9N5OS: C, 50.96; H, 3.5; N, 27.01; S, 12.37. Found: C, 51.74; H,
3.34; N, 27.05; S, 12.30.
Compound 4.5
IR (cm–1): 3324, 3029, 1668, 1621, 1551, 1478, 1396, 1385, 1264,
1210, 1199, 1120, 1078, 1049, 1017, 904, 781, 736, 719, 695, 645;
1H-NMR (400 MHz) d: 9.49 (s, 1H, H-5), 8.37 (d, J = 6.8 Hz, 1H, H-
10), 8.70 (m, 1H, NH), 8.03 (d, J = 8.0 Hz, 1H, H-7), 7.92 (t, J =
7.8 Hz, 1H, H-8), 7.80 (t, J = 7.8 Hz, 1H, H-9), 4.15 (s, 2H, SCH2), 4.07
(q, J = 6.8 Hz, 2H, OCH2), 3.89 (d, J = 7.8 Hz, 2H, NCH2), 1.15 (t, J =
6.8 Hz, 3H, CH3); LC-MS m/z: 250 [M + H]+, 252. Anal. calcd. for
C18H15N5OS: C, 61.87; H, 4.33; N, 20.04; S, 9.18. Found: 61.78; H,
4.30; N, 20.10; S, 9.22.
Compound 4.2
IR (cm–1): 3330, 3061, 2955, 2930, 2860, 1651, 1621, 1537, 1511,
1477, 1392, 1356, 1315, 1264, 1197, 1103, 958, 902, 782, 767,
734, 714, 731, 631; 1H-NMR (400 MHz) d: 9.49 (s, 1H, H-5), 8.38 (d,
J = 7.8 Hz, 1H, H-10), 8.22 (m, 1H, NH), 8.05 (d, J = 7.8 Hz, 1H, H-7),
7.94 (t, J = 8.1 Hz, 1H, H-8), 7.82 (t, J = 7.8 Hz, 1H, H-9), 4.05 (s, 2H,
SCH2), 3.08 (q, J = 7.8 Hz, 2H, NCH2), 1.37 (q, J = 7.8 Hz, 2H,
NCH2CH2), 1.24 (sext, 2H, N(CH2)2CH2), 0.80 (t, J = 7.8 Hz, 3H,
CH2CH3); LC-MS m/z: 316 [M + H]+. Anal. calcd. for C15H17N5OS: C,
57.12; H, 5.43; N, 22.20; S, 10.17. Found: C, 57.07; H, 5.49; N,
22.28; S, 10.13.
Compound 4.6
IR (cm–1): 3292, 3056, 2971, 1742, 1683, 1657, 1624, 1600, 1558,
1518, 1477, 1395, 1372, 1304, 1263, 1186, 1104, 1022, 891, 768,
718, 642;1H-NMR (400 MHz) d: 9.49 (s, 1H, H-5), 8.37 (d, J = 8.0 Hz,
1H, H-10), 8.70 (m, 1H, NH), 8.03 (d, J = 8.0 Hz, 1H, H-7), 7.92 (t, J =
7.8 Hz, 1H, H-8), 7.80 (t, J = 7.8 Hz, 1H, H-9), 4.15 (s, 2H, SCH2), 4.07
(q, J = 6.8 Hz, 2H, OCH2), 3.89 (d, J = 7.8 Hz, 2H, NCH2), 1.15 (t, J =
6.8 Hz, 3H, CH3); LC-MS m/z: 346 [M + H]+, 348; EI-MS m/z (I,%): 346
(13.3), 345 (47.3) [M]+, 300 (6.4), 243 (30.2), 242 (19.5), 218 (5.7),
217 (14.7), 216 (100.0), 215 (69.2), 203 (6.8), 202 (17.9), 187 (8.2),
i 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

658
L. N. Antipenko et al.
Arch. Pharm. Chem. Life Sci. 2009, 342, 651–662
184 (8.0), 171 (20.8), 130 (12.1), 129 (33.0), 102 (23.1). Anal. calcd.
for C15H15N5O3S: C, 52.16; H, 4.38; N, 20.28; S, 9.27. Found: C,
52.20; H, 4.55; N, 20.17; S, 9.29.
Compound 4.12
IR (cm–1): 3312, 3057, 2995, 2930, 2828, 1669, 1602, 1537, 1476,
1458, 1398, 1384, 1353, 1250, 1216, 1171, 1103, 1034, 959, 898,
851, 771, 754, 716, 703, 642; 1H-NMR (400 MHz) d: 9.60 (br.s, 1H,
NH), 9.51 (s, 1H, H-5), 8.39 (d, J = 7.8 Hz, 1H, H-10), 8.04 (d, J =
7.8 Hz, 1H, H-7), 8.01 (d, J = 7.8 Hz, 1H, H-6Ph), 7.93 (t, J = 7.8 Hz,
1H, H-8), 7.81 (t, J = 7.8 Hz, 1H, H-9), 7.03 (m, 3H, H-3Ph,5Ph,6Ph),
6.88 (t, J = 7.8 Hz, 1H, H-4Ph), 4.34 (s, 2H, SCH2), 3.77 (s, 3H, OCH3);
LC-MS m/z: 366 [M + H]+. Anal. calcd. for C18H15N5O2S: C, 59.17; H,
4.14; N, 19.,17; S, 8.77. Found: C, 59.12; H, 4.17; N, 19.15; S, 8.73.
Compound 4.7
IR (cm–1): 3060, 2944, 2922, 2852, 2310, 1636, 1622, 1602, 1515,
1476, 1437, 1395, 1354, 1309, 1242, 1199, 1132, 1007, 899, 851,
1
816, 766, 715, 645, 616; H-NMR (400 MHz) d: 9.51 (s, 1H, H-5),
8.38 (d, J = 7.8 Hz, 1H, H-10), 8.03 (d, J = 7.8 Hz, 1H, H-7), 7.92 (t, J =
7.8 Hz, 1H, H-8), 7.80 (t, J = 7.8 Hz, 1H, H-9), 4.42 (s, 2H, SCH2), 3.51
(t, J = 5.1 Hz, 2H, CH2-6pip), 3.45 (t, J = 5.1 Hz, 2H, CH2-2pip), 1.59 (m,
4H, (CH2)2-3,5pip), 1.59 (m, 2H, CH2-4pip); LC-MS m/z: 328 [M + H]+.
Anal. calcd. for C16H17N5OS: C, 58.70; H, 5.23; N, 21.37; S, 9.79.
Found: C, 58.75; H, 5.29; N, 21.30; S, 9.72.
Compound 4.13
IR (cm–1): 3306, 3113, 3061, 2977, 1678, 1595, 1533, 1477, 1417,
1402, 1387, 1356, 1250, 1218, 1171, 1127, 1033, 959, 899, 873,
811, 774, 716, 642; 1H-NMR (400 MHz) d: 9.70 (br.s, 1H, NH), 9.50
(s, 1H, H-5), 8.39 (d, J = 7.8 Hz, 1H, H-10), 8.13 (s, 1H, H-3Ph), 8.05
(d, J = 7.8 Hz, 1H, H-7), 7.94 (t, J = 7.8 Hz, 1H, H-8), 7.82 (t, J =
7.8 Hz, 1H, H-9), 7.09 (d, J = 8.1 Hz, 1H, H-5Ph), 7.04 (d, J = 8.1 Hz,
1H, H-6Ph), 4.35 (s, 2H, SCH2), 3.79 (s, 3H, OCH3); LC-MS m/z: 400 [M
+ H]+, 401. Anal. calcd. for C18H14ClN5O2S: C, 54.07; H, 5.53; N,
17.51; S, 8.02. Found: C, 54.14; H, 5.49; N, 17.56; S, 8.05.
Compound 4.8
IR (cm–1): 3063, 2987, 2896, 2850, 1623, 1515, 1455, 1397, 1356,
1283, 1253, 203, 1183, 1104, 1066, 1048, 1030, 959, 900, 871,
841, 773, 716, 645;1H-NMR (400 MHz) d: 9.44 (s, 1H, H-5), 8.38 (d, J
= 7.8 Hz, 1H, H-10), 8.04 (d, J = 7.8 Hz, 1H, H-7), 7.93 (t, J = 7.6 Hz,
1H, H-8), 7.81 (t, J = 7.6 Hz, 1H, H-9), 4.39 (s, 2H, SCH2), 3.63 (m,
4H, (CH2)2-2,6morph), 3.56 (m, 4H, (CH2)2-3,5morph); LC-MS m/z: 330 [M
+ H]+. Anal. calcd. for C15H15N5O2S: C, 57.70; H, 4.59; N, 21.26; S,
9.73. Found: C, 57.72; H, 4.55; N, 21.30; S, 9.68.
Compound 4.14
IR (cm–1): 3362, 3071, 2996, 2939, 1697, 1607, 1585, 1502, 1452,
1
1398, 1373, 1338, 1266, 1145, 956, 900, 781, 750, 717, 643; H-
NMR (400 MHz) d: 10.75 (br.s, 1H, NH), 9.49 (s, 1H, H-5), 8.39 (d, J =
8.0 Hz, 1H, H-10), 8.04 (d, J = 8.0 Hz, 1H, H-7), 7.98 (d, J = 7.8 Hz,
1H, H-6Ph), 7.93 (t, J = 8.0 Hz, 1H, H-8), 7.88 (d, J = 7.8 Hz, 1H, H-
3Ph), 7.81 (t, J = 8.0 Hz, 1H, H-9), 7.72 (t, J = 7.8 Hz, 1H, H-5Ph), 7.36
(t, J = 7.8 Hz, 1H, H-4Ph), 4.33 (s, 2H, SCH2); LC-MS m/z: 381 [M + H]+,
383. Anal. calcd. for C17H12N6O3S: C, 53.68; H, 3.18; N, 22.09; S,
8.43. Found: C, 53.61; H, 3.26; N, 22.10; S, 8.50.
Compound 4.9
IR (cm–1): 3325, 3052, 3024, 1674, 1600, 1543, 1516, 1475, 1442,
1391, 1326, 1263, 1244, 1176, 1103, 965, 941, 941, 902, 778, 756,
718, 690, 642; 1H-NMR (400 MHz) d: 10.38 (br.s, 1H, NH), 9.50 (s,
1H, H-5), 8.38 (d, J = 8.0 Hz, 1H, H-10), 8.05 (d, J = 8.0 Hz, 1H, H-7),
7.94 (t, J = 7.8 Hz, 1H, H-8), 7.81 (t, J = 7.8 Hz, 1H, H-9), 7.60 (d, J =
7.8 Hz, 2H, H-2Ph,6Ph), 7.31 (t, J = 7.8 Hz, 2H, H-3Ph,5Ph), 7.05 (t, J =
7.3 Hz, 1H, H-4Ph), 4.32 (s, 2H, SCH2); LC-MS m/z: 336 [M + H]+, 338.
Anal. calcd. for C17H13N5OS: C, 60.88; H, 3.91; N, 20.88; S, 9.56.
Found: C, 60.80; H, 3.96; N, 20.81; S, 9.49.
Compound 4.15
IR (cm–1): 3321, 3078, 3053, 2919, 2310, 1673, 1612, 1545, 1499,
1451, 1392, 1331, 1248, 1164, 1106, 955, 934, 901, 851, 769, 749,
716, 684, 629; 1H-NMR (400 MHz) d: 11.03 (br.s, 1H, NH), 9.50 (s,
1H, H-5), 8.36 (d, J = 7.8 Hz, 1H, H-10), 8.23 (d, J = 9.0 Hz, 2H, H-
2Ph,6Ph), 8.04 (d, J = 7.8 Hz, 1H, H-7), 7.94 (t, J = 8.0 Hz, 1H, H-8),
7.85 (d, J = 9.0 Hz, 2H, H-3Ph,5Ph), 7.81 (t, J = 8.0 Hz, 1H, H-9), 4.39
(s, 2H, SCH2); LC-MS m/z: 380 [M + H]+. Anal. calcd. for C17H12N6O3S:
C, 53.68; H, 3.18; N, 22.09; S, 8.43. Found: C, 53.58; H, 3.21; N,
22.20; S, 8.45.
Compound 4.10
IR (cm–1): 3343, 3054, 2975, 2919, 2850, 1670, 1589, 1538, 1513,
1474, 1450, 1396, 1371, 1263, 1246, 1189, 1174, 1102, 1046, 955,
895, 852, 766, 716, 664; 1H-NMR (400 MHz) d: 9.71 (br.s, 1H, NH),
9.50 (s, 1H, H-5), 8.38 (d, J = 8.1 Hz, 1H, H-10), 8.04 (d, J = 8.1 Hz,
1H, H-7), 7.93 (t, J = 8.1 Hz, 1H, H-8), 7.81 (t, J = 8.1 Hz, 1H, H-9),
7.43 (d, J = 7.8 Hz, 1H, H-6Ph), 7.19 (d, J = 7.8 Hz, 1H, H-3Ph), 7.15 (t, J
= 7.6 Hz, 1H, H-5Ph), 7.07 (t, J = 7.8 Hz, 1H, H-4Ph), 4.34 (s, 2H, SCH2)
3.32 (s, 3H, CH3); LC-MS m/z: 350 [M + H]+. Anal. calcd. for
C18H15N5OS: C, 61.87; H, 4.33; N, 20.04; S, 9.18. Found: 61.78; H,
4.30; N, 20.10; S, 9.22.
Compound 4.16
IR (cm–1): 3296, 3255, 3187, 3065, 1682, 1594, 1546, 1516, 1479,
1404, 1334, 1255, 1191, 1131, 1101, 901, 767, 715, 685, 611; 1H-
NMR (400 MHz) d: 10.60 (br.s, 1H, NH), 9.50 (s, 1H, H-5), 8.37 (d, J =
6.0 Hz, 1H, H-10), 8.04 (d, J = 6.0 Hz, 1H, H-7), 7.93 (t, J = 7.8 Hz,
1H, H-8), 7.81 (t, J = 7.8 Hz, 1H, H-9), 7.80 (t, J = 7.6 Hz, 1H, H-2Ph),
7.47 (d, J = 7.8 Hz, 1H, H-6Ph), 7.35 (t, J = 7.8 Hz, 1H, H-5Ph), 7.12 (t,
J = 7.8 Hz, 1H, H-4Ph), 4.33 (s, 2H, SCH2); LC-MS m/z: 370 [M + H]+,
372, 374. Anal. calcd. for C15H12ClN5OS: C, 55.21; H, 3.27; N,
18.94; S, 8.67. Found: C, 55.23; H, 3.37; N, 19.02; S, 8.62.
Compound 4.11
IR (cm–1): 3290, 3257, 3198, 3064, 2920, 1665, 1614, 1555, 1515,
1478, 1402, 1384, 371, 1328, 1306, 1253, 1197, 1168, 1130, 900,
786, 765, 714, 695, 615;1H-NMR (400 MHz) d: 10.31 (br.s, 1H, NH),
9.47 (s, 1H, H-5), 8.34 (d, J = 7.8 Hz, 1H, H-10), 8.00 (d, J = 7.8 Hz,
1H, H-7), 7.89 (t, J = 7.8 Hz, 1H, H-8), 7.77 (t, J = 7.8 Hz, 1H, H-9),
7.44 (s, 1H, H-2Ph), 7.38 (d, J = 7.8 Hz, 1H, H-6Ph), 7.17 (t, J = 7.8 Hz,
1H, H-5Ph), 6.85 (d, J = 7.8 Hz, 1H, H-4Ph), 4.31 (s, 2H, SCH2), 2.25 (s,
3H, CH3); LC-MS m/z: 350 [M + H]+. Anal. calcd. for C18H15N5OS: C,
61.87; H, 4.33; N, 20.04; S, 9.18. Found: 61.78; H, 4.30; N, 20.10; S,
9.22.
Compound 4.17
IR (cm–1): 3302, 3060, 1666, 1621, 1593, 1512, 1490, 1478, 1393,
1318, 1264, 1238, 1168, 1093, 1013, 966, 903, 820, 770, 715,667,
1
648; H-NMR (400 MHz) d: 10.44 (br.s, 1H, NH), 9.47 (s, 1H, H-5),
8.37 (d, J = 7.8 Hz, 1H, H-10), 8.04 (d, J = 7.8 Hz, 1H, H-7), 7.93 (t, J =
i 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2009, 342, 651–662
2-Thio-[1,2,4]triazolo[1,5-c]quinazolines
659
7.6 Hz, 1H, H-8), 7.81 (t, J = 7.6 Hz, 1H, H-9), 7.62 (d, J = 8.1 Hz, 2H,
H-2Ph,6Ph), 7.35 (d, J = 8.1 Hz, 2H, H-3Ph,5Ph), 4.31 (s, 2H, SCH2); LC-
MS m/z: 370 [M + H]+, 372, 374; EI-MS m/z (I,%): 369 (10.2) [M]+, 245
(8.0), 244 (16.5), 243 (100.0), 242 (9.3), 217 (5.8), 216 (33.7), 215
(58.7), 171 (8.3), 130 (6.3), 129 (26.4), 127 (11.3), 102 (10.1), 99
(8.9). Anal. calcd. for C15H12ClN5OS: C, 55.21; H, 3.27; N, 18.94; S,
8.67. Found: C, 55.23; H, 3.37; N, 19.02; S, 8.62.
3H, SCHCH3), 1.37 (q, J = 7.8 Hz, 2H, NCH2CH2), 1.23 (sext, 2H,
N(CH2)2CH2), 0.80 (t, J = 7.8 Hz, 3H, CH2CH3); LC-MS m/z: 330 [M +
H]+, 331. Anal. calcd. for C16H19N5OS: C, 58.34; H, 5.81; N, 21.26; S,
9.73. Found: C, 58.28; H, 5.76; N, 21.28; S, 9.79.
Compound 5.2
IR (cm–1): 3318, 2965, 1656, 1625, 1545, 1521, 1478, 1455, 1398,
1358, 1272, 1249, 1226, 989, 901, 784, 769, 715; 1H-NMR
(400 MHz) d: 9.51 (s, 1H, H-5), 8.39 (d, J = 7.8 Hz, 1H, H-10), 8.06 (d,
J = 7.8 Hz, 1H, H-7), 8.00 (br.s, 1H, NH), 7.94 (t, J = 7.8 Hz, 1H, H-8),
7.82 (t, J = 7.8 Hz, 1H, H-9), 4.57 (q, J = 6.8 Hz, 1H, SCH), 1.58 (d, J =
6.8 Hz, 3H, SCHCH3), 1.25 (s, 9H, (CH3)3); LC-MS m/z: 330 [M + H]+;
EI-MS m/z (I,%): 257 (4.4), 232 (4.3), 231 (12.3), 230 (100.0), 229
(28.8), 215 (23.9), 202 (6.9), 198 (11.7), 197 (65.7), 171 (36.9), 170
(4.9), 145 (5.3), 130 (3.3), 129 (26.5), 102 (15.8), 101 (5.4), 75 (3.6),
72 (4.8), 60 (7.9), 59 (23.6), 58 (10.3), 57 (47.0), 55 (8.2). Anal. calcd.
for C16H19N5OS: C, 58.34; H, 5.81; N, 21.26; S, 9.73. Found: C,
58.28; H, 5.76; N, 21.28; S, 9.79.
Compound 4.18
IR (cm–1): 3309, 3052, 2918, 1664, 1619, 1591, 1531, 1518, 1474,
1391, 1303, 1262, 1243, 1119, 1072, 1008, 902, 818, 775, 717,
642; 1H-NMR (400 MHz) d: 10.55 (br.s, 1H, NH), 9.51 (s, 1H, H-5),
8.37 (d, J = 8.0 Hz, 1H, H-10), 8.05 (d, J = 8.0 Hz, 1H, H-7), 7.94 (t, J =
7.8 Hz, 1H, H-8), 7.82 (t, J = 7.8 Hz, 1H, H-9), 7.58 (d, J = 8.0 Hz, 2H,
H-2Ph,6Ph), 7.50 (d, J = 8.0 Hz, 2H, H-3Ph,5Ph), 4.33 (s, 2H, SCH2); LC-
MS m/z: 416 [M + H]+, 417. Anal. calcd. for C17H12N5OS: C, 49.29; H,
2.92; N, 16.90; S, 7.74. Found: C, 49.30; H, 2.95; N, 16.98; S, 7.65.
Compound 4.19
IR (cm–1): 3295, 3264, 3204, 3148, 3066, 1681, 1668, 1619, 1602,
1553, 1479, 1403, 1327, 1313, 1253, 1185, 1169, 1115, 1094,
1072, 900, 766, 703; 1H-NMR (400 MHz) d: 10.73 (br.s, 1H, NH),
9.49 (s, 1H, H-5), 8.36 (d, J = 7.8 Hz, 1H, H-10), 8.09 (s, 1H, H-2Ph),
8.04 (d, J = 7.8 Hz, 1H, H-7), 7.93 (t, J = 7.8 Hz, 1H, H-8), 7.80 (t, J =
7.8 Hz, 2H, H-9, H-6Ph), 7.56 (t, J = 8.0 Hz, 1H, H-5Ph), 7.41 (d, J =
8.0 Hz, 1H, H-4Ph), 4.34 (s, 2H, SCH2); LC-MS m/z: 404 [M + H]+, 405.
Anal. calcd. for C18H12F3N5OS: C, 53.60; H, 3.0; N, 17.33; S, 7.95.
Found: C, 53.65; H, 2.97; N, 17.28; S, 7.98.
Compound 5.3
IR (cm–1): 3292, 3056, 2932, 1634, 1620, 1542, 1510, 1477, 1453,
1
1386, 1372, 1251, 1203, 1079, 963, 900, 778, 746, 696, 643; H-
NMR (400 MHz) d: 9.49 (s, 1H, H-5), 8.84 (t, J = 6.6 Hz, 1H, NH),
8.36 (d, J = 7.8 Hz, 1H, H-10), 8.04 (d, J = 7.8 Hz, 1H, H-7), 7.93 (t, J =
7.8 Hz, 1H, H-8), 7.81 (t, J = 7.8 Hz, 1H, H-9), 7.21 (s, 5H, Ph), 7.16
(d, J = 7.8 Hz, 1H, H-3Ph), 7.09 (t, J = 7.8 Hz, 1H, H-4Ph), 4.65 (q, J =
6.8 Hz, 1H, SCH), 4.31 (d, J = 8.6 Hz, 2H, NCH2), 1.65 (d, J = 6.8 Hz,
3H, SCHCH3); LC-MS m/z: 364 [M + H]+, 365. Anal. calcd. for
C19H17N5OS: C, 62.79; H, 4.71; N, 19.27; S, 8.82. Found: C, 62.78;
H, 4.60; N, 19.18; S, 8.72.
Compound 4.20
IR (cm–1): 3250, 3181, 3053, 2982, 2907, 2862, 1689, 1626, 1597,
1546, 1513, 1479, 1398, 1267, 1253, 1169, 1118, 1102, 1024, 901,
858, 765, 712, 639, 613;1H-NMR (400 MHz) d: 10.75 (br.s, 1H, NH),
9.50 (s, 1H, H-5), 8.36 (d, J = 7.8 Hz, 1H, H-10), 8.04 (d, J = 7.8 Hz,
1H, H-7), 7.92 (t, J = 8.6 Hz, 3H, H-8, H-2Ph,6Ph), 7.80 (t, J = 7.8 Hz,
1H, H-9), 7.74 (d, J = 8.6 Hz, 2H, H-3Ph,5Ph), 4.36 (s, 2H, SCH2), 4.27
(q, J = 7.1 Hz, 2H, CH2CH3), 1.29 (t, J = 7.1 Hz, 3H, CH3); LC-MS m/z:
408 [M + H]+, 409. Anal. calcd. for C20H17N5O3S: C, 58.96; H, 4.21;
N, 17.19; S, 7.87. Found: C, 58.65; H, 4.30; N, 17.29; S, 7.88.
Compound 5.4
IR (cm–1): 3067, 3009, 2984, 2941, 2860, 1623, 1518, 1476, 1440,
1395, 1350, 1301, 1253, 1135, 1104, 1056, 1012, 953, 922, 897,
850, 765, 714, 644, 622; 1H-NMR (400 MHz) d: 9.52 (s, 1H, H-5),
8.39 (d, J = 7.8 Hz, 1H, H-10), 8.04 (d, J = 7.8 Hz, 1H, H-7), 7.93 (t, J =
7.8 Hz, 1H, H-8), 7.81 (t, J = 7.8 Hz, 1H, H-9), 5.05 (q, J = 6.8 Hz, 1H,
SCH), 3.53 (m, 4H, (CH2)2-2,6pip), 1.61 (m, 6H, (CH2)3-3pip,4pip,5pip),
1.45 (d, J = 6.8 Hz, 3H, SCHCH3); LC-MS m/z: 342 [M + H]+; EI-MS m/z
(I,%): 229 (10.3), 203 (8.3), 202 (6.9), 141 (8.6), 140 (100.0), 139
(21.2), 129 (9.4), 112 (50.4), 111 (9.3), 102 (7.4), 84 (31.7), 83 (5.9),
70 (6.8), 69 (62.8), 59 (13.1), 56 (14.2), 55 (13.2). Anal. calcd. for
C17H19N5OS: C, 59.80; H, 5.61; N, 20.51; S, 9.39. Found: C, 59.81;
H, 5.64; N, 20.47; S, 9.31.
Compound 4.21
IR (cm–1): 3058, 2964, 2929, 1638, 1554, 1515, 1477, 1453, 1396,
1310, 1269, 1228, 1133, 1105, 952, 899, 767, 715, 645, 614; 1H-
NMR (400 MHz) d: 9.47 (s, 1H, H-5), 8.37 (d, J = 8.0 Hz, 1H, H-10),
8.04 (d, J = 8.0 Hz, 1H, H-7), 7.93 (t, J = 7.8 Hz, 1H, H-8), 7.81 (t, J =
7.8 Hz, 1H, H-9), 4.38 (s, 2H, SCH2), 3.47 (m, NCH2), 3.33 (m, NCH2),
1.24 (t, J = 7.8 Hz, 3H, CH3), 1.05 (t, J = 7.8 Hz, 3H, CH3); LC-MS m/z:
316 [M + H]+; EI-MS m/z (I,%): 316 (15.9), 315 (47.2) [M]+, 243 (10.1),
242 (5.9), 216 (12.6), 215 (31.5), 203 (9.5), 202 (37.8), 171 (8.3), 130
(7.6), 129 (20.4), 115 (10.8), 114 (100.0), 102 (15.4), 100 (92.0).
Anal. calcd. for C15H17N5OS: C, 57.12; H, 5.43; N, 22.20; S, 10.17.
Found: C, 57.07; H, 5.49; N, 22.28; S, 10.13.
Compound 5.5
IR (cm–1): 3050, 2976, 2952, 2906, 2859, 2310, 1643, 1617, 1512,
1475, 1428, 1396, 1302, 1217, 1105, 1062, 1025, 968, 939, 896,
844, 779, 717, 644; 1H-NMR (400 MHz) d: 9.53 (s, 1H, H-5), 8.40 (d,
J = 7.8 Hz, 1H, H-10), 8.06 (d, J = 7.8 Hz, 1H, H-7), 7.95 (t, J = 7.8 Hz,
1H, H-8), 7.83 (t, J = 7.8 Hz, 1H, H-9), 5.04 (q, J = 6.8 Hz, 1H, SCH),
3.64 (m, 4H, (CH2)2-2morph,6morph), 3.52 (m, 4H, (CH2)2-3morph,5morph),
1.61 (d, J = 6,8 Hz, 3H, SCHCH3); LC-MS m/z: 344 [M + H]+. Anal.
calcd. for C16H19N5O2S: C, 55.96; H, 4.99; N, 20.39; S, 9.34. Found:
C, 56.01; H, 5.05; N, 20.29; S, 9.44.
Compound 5.1
IR (cm–1): 3336, 3056, 2970, 2957, 2931, 2873, 1642, 1626, 1546,
1521, 1478, 1454, 1384, 1306, 1267, 1215, 1105, 1079, 992, 961,
900, 771, 716, 615; 1H-NMR (400 MHz) d: 9.51 (s, 1H, H-5), 8.39 (d, J
= 8.0 Hz, 1H, H-10), 8.29 (t, J = 6.8 Hz, 1H, NH), 8.05 (d, J = 7.80 Hz,
1H, H-7), 7.94 (t, J = 7.8 Hz, 1H, H-8), 7.82 (t, J = 7.8 Hz, 1H, H-9),
4.56 (q, J = 6.8 Hz, 1H, SCH), 3.07 (m, 2H, NCH2), 1.60 (d, J = 6.8 Hz,
Compound 5.6
IR (cm–1): 3274, 3165, 3131, 3042, 2982, 2935, 1686, 1600, 1550,
1516, 1476, 1442, 1371, 1339, 1300, 1252, 1173, 1074, 900, 778,
755, 717, 695, 642;1H-NMR (400 MHz) d: 10.42 (br.s, 1H, NH), 9.53
i 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

660
L. N. Antipenko et al.
Arch. Pharm. Chem. Life Sci. 2009, 342, 651–662
(s, 1H, H-5), 8.40 (d, J = 8.1 Hz, 1H, H-10), 8.06 (d, J = 8.1 Hz, 1H, H-
7), 7.95 (t, J = 7.8 Hz, 1H, H-8), 7.83 (t, J = 7.8 Hz, 1H, H-9), 7.60 (d,
J = 8.1 Hz, 2H, H-2Ph,6Ph), 7.31 (d, J = 7.3 Hz, 2H, H-3Ph,5Ph), 7.07 (t, J
= 7.3 Hz, 1H, H-4Ph), 4.80 (q, J = 6.6 Hz, 1H, SCH), 1.72 (d, J = 6.6 Hz,
3H, SCHCH3); LC-MS m/z: 350 [M + H]+. Anal. calcd. for C18H15N5OS:
C, 61.87; H, 4.33; N, 20.04; S, 9.18. Found: C, 61.83; H, 4.35; N,
20.10; S, 9.14.
(400 MHz) d: 10.56 (br.s, 1H, NH), 9.52 (s, 1H, H-5), 8.39 (d, J =
7.8 Hz, 1H, H-10), 8.06 (d, J = 7.8 Hz, 1H, H-7), 7.94 (t, J = 7.8 Hz,
1H, H-8), 7.82 (t, J = 7.6 Hz, 1H, H-9), 7.64 (d, J = 8.6 Hz, 2H, H-
2Ph,6Ph), 7.37 (d, J = 8.0 Hz, 2H, H-3Ph,5Ph), 4.77 (q, J = 6.8 Hz, 1H,
SCH), 1.72 (d, J = 6.8 Hz, 3H, SCHCH3); LC-MS m/z: 384 [M + H]+,
385. Anal. calcd. for C18H14ClN5OS: C, 56.32; H, 3.68; N, 18.24; S,
8.35. Found: C, 56.24; H, 3.65; N, 18.18; S, 8.30.
Compound 5.12
Compound 5.7
IR (cm–1): 3298, 3090, 2982, 1662, 1623, 1547, 1518, 1478, 1455,
1396, 1374, 1328, 1265, 1223, 1160, 1116, 991, 877, 796, 771,
695, 651; 1H-NMR (400 MHz) d: 10.79 (br.s, 1H, NH), 9.52 (s, 1H, H-
5), 8.38 (d, J = 7.8 Hz, 1H, H-10), 8.1 (s, 1H, H-2Ph), 8.05 (d, J =
7.8 Hz, 1H, H-7), 7.94 (t, J = 7.8 Hz, 1H, H-8), 7.81 (t, J = 7.8 Hz, 2H,
H-9, H-6Ph), 7.56 (t, J = 7.8 Hz, 1H, H-5Ph), 7.42 (d, J = 7.8 Hz, 1H, H-
4Ph), 4.78 (q, J = 6.8 Hz, 1H, SCH), 1.73 (d, J = 6.8 Hz, 3H, SCHCH3);
LC-MS m/z: 418 [M + H]+; EI-MS m/z (I,%): 418 (8.2) [M+1]+, 258 (6.9),
257 (56.7), 232 (4.3), 231 (13.6), 230 (100.0), 229 (54.2), 215 (19.2),
212 (5.0), 203 (3.4), 202 (13.6), 198 (8.4), 197 (69.3), 171 (26.5), 170
(5.0), 161 (5.8), 145 (8.1), 130 (3.0), 129 (27.2), 102 (16.6), 101 (6.6),
75 (5.0), 69 (11.9), 59 (29.9), 55 (8.9). Anal. calcd. for C19H14F3N5OS:
C, 54.67; H, 3.38; N, 16.78; S, 7.68. Found: C, 54.60; H, 3.29; N,
16.80; S, 7.61.
IR (cm–1): 3260, 3068, 2964, 2843, 1655, 1623, 1590, 1537, 1517,
1478, 1453, 1392, 1374, 1347, 1302, 1264, 1185, 1085, 992, 901,
773, 754, 717, 677; 1H-NMR (400 MHz) d: 9.78 (br.s, 1H, NH), 9.54
(s, 1H, H-5), 8.42 (d, J = 7.8 Hz, 1H, H-10), 8.07 (d, J = 7.8 Hz, 1H, H-
7), 7.95 (t, J = 7.6 Hz, 1H, H-8), 7.83 (t, J = 7.6 Hz, 1H, H-9), 7.40 (d,
J = 8.0 Hz, 1H, H-6Ph), 7.20 (d, J = 8.0 Hz, 1H, H-5Ph), 7.16 (d, J =
7.8 Hz, 1H, H-3Ph), 7.09 (t, J = 7.8 Hz, 1H, H-4Ph), 4.88 (q, J = 6.8 Hz,
1H, SCH), 3.33 (s, 3H, CH3), 1.74 (d, J = 6.8 Hz, 3H, SCHCH3); LC-MS
m/z: 364 [M + H]+, 366. Anal. calcd. for C19H17N5OS: C, 62.79; H,
4.71; N, 19.27; S, 8.82. Found: C, 62.74; H, 4.65; N, 19.23; S, 8.78.
Compound 5.8
IR (cm–1): 3307, 3055, 3032, 2970, 2920, 1662, 1624, 1543, 1518,
1477, 1451, 1392, 1303, 1262, 1197, 1074, 997, 901, 770, 717,
690, 640; 1H-NMR (400 MHz) d: 10.38 (br.s, 1H, NH), 9.53 (s, 1H, H-
5), 8.40 (d, J = 8.0 Hz, 1H, H-10), 8.06 (d, J = 8.0 Hz, 1H, H-7), 7.94 (t,
J = 7.8 Hz, 1H, H-8, Ph), 7.82 (t, J = 7.8 Hz, 1H, H-9), 7.46 (s, 1H, H-
2Ph), 7.40 (d, J = 7.6 Hz, 1H, H-6Ph), 7.19 (t, J = 7.6 Hz, 1H, H-5Ph),
6.89 (d, J = 7.6 Hz, 1H, H-4Ph), 4.80 (q, J = 6.8 Hz, 1H, SCH), 2.27 (s,
3H, CH3), 1.72 (d, J = 6.8 Hz, 3H, SCHCH3); LC-MS m/z: 364 [M + H]+,
366. Anal. calcd. for C19H17N5OS: C, 62.79; H, 4.71; N, 19.27; S,
8.82. Found: C, 62.74; H, 4.65; N, 19.23; S, 8.78.
Compound 6.1
IR (cm–1): 3284, 3195, 3136, 3058, 2983, 2947, 2918, 1661, 1623,
1603, 1539, 1519, 1487, 1476, 1454, 1412, 1394, 1386, 1373,
1353, 1301, 1257, 1191, 1149, 1127, 1103, 1042, 988, 965, 925,
900, 880, 797, 772, 755, 717, 700, 641; 1H-NMR (500 MHz) d: 9.53
(s, 1H, H-5), 8.38 (d, J = 7.8 Hz, 1H, H-10), 8.04 (d, J = 7.9 Hz, 1H, H-
7), 7.93 (t, J = 8.0 Hz, 1H, H-8), 7.80 (t, J = 8.0 Hz, 1H, H-9), 3.53 (m,
4H, SCH2, H-2morph,6morph), 3.44 (m, 4H, H-3morph,5morph), 2.88 (t, J =
6.8 Hz, 2H, SCH2CH2); LC-MS m/z: 334 [M + H]+, 336. Anal. calcd.
for C19H17N5OS: C, 62.79; H, 4.71; N, 19.27; S, 8.82. Found: C,
62.74; H, 4.65; N, 19.23; S, 8.78.
Compound 5.9
IR (cm–1): 3305, 3050, 2981, 2933, 1679, 1604, 1538, 1513, 1480,
1460, 1453, 1396, 1377, 1264, 1251, 1220, 1173, 1107, 1026, 921,
899, 770, 736, 718, 701; 1H-NMR (400 MHz) d: 9.61 (br.s, 1H, NH),
9.54 (s, 1H, H-5), 8.43 (d, J = 8.1 Hz, 1H, H-10), 8.07 (d, J = 8.1 Hz,
1H, H-7), 7.99 (d, J = 7.8 Hz, 1H, H-6Ph), 7.96 (t, J = 7.6 Hz, 1H, H-8),
7.85 (t, J = 7.6 Hz, 1H, H-9), 7.06 (t, J = 7.6 Hz, 1H, H-5Ph), 6.99 (d, J =
7.8 Hz, 1H, H-3Ph), 6.89 (t, J = 7.8 Hz, 1H, H-4Ph), 7.09 (t, J = 7.8 Hz,
1H, H-4Ph), 4.95 (q, J = 6.8 Hz, 1H, SCH), 3.71 (s, 3H, OCH3), 1.67 (d, J
= 6.8 Hz, 3H, SCHCH3); LC-MS m/z: 380 [M + H]+. Anal. calcd. for
C19H17N5O2S: C, 60.14; H, 4.52; N, 18.46; S, 8.45. Found: C, 60.18;
H, 4.42; N, 18.37; S, 8.49.
Compound 6.2
IR (cm–1): 3059, 2295, 2966, 2860, 1649, 1624, 1513, 1479, 1449,
1392, 1371, 1353, 1299, 1244, 1208, 1186, 1111, 1069, 1028, 984,
959, 913, 897, 852, 817, 781, 764, 715, 640; 1H-NMR (500 MHz) d:
9.88 (br.s, 1H, NH), 9.54 (s, 1H, H-5), 8.39 (d, J = 7.8 Hz, 1H, H-10),
8.04 (d, J = 7.8 Hz, 1H, H-7), 7.93 (t, J = 7.8 Hz, 1H, H-8), 7.80 (t, J =
7.8 Hz, 1H, H-9), 7.40 (s, 1H, H-2Ph), 7.34 (d, J = 7.9 Hz, 1H, H-6Ph),
7.14 (t, J = 7.9 Hz, 1H, H-5Ph), 6.83 (d, J = 7.8 Hz, 1H, H-4Ph), 3.53 (t, J
= 6.9 Hz, 2H, SCH2), 2.90 (t, J = 6.8 Hz, 2H, SCH2CH2), 2.24 (s, 3H,
CH3); LC-MS m/z: 344 [M + H]+, 346. Anal. calcd. for C16H17N5O2S: C,
55.96; H, 4.99; N, 20.39; S, 9.34. Found: C, 55.76; H, 5.09; N, 20.35;
S, 9.62.
Compound 5.10
IR (cm–1): 3273, 3218, 3089, 1696, 1625, 1597, 1569, 1500, 1442,
1393, 1338, 1262, 1210, 1172, 1116, 1075, 900, 851, 768, 750,
716, 689; 1H-NMR (400 MHz) d: 11.05 (br.s, 1H, NH), 9.53 (s, 1H, H-
5), 8.38 (d, J = 8.6 Hz, 1H, H-10), 8.06 (d, J = 8.6 Hz, 1H, H-7), 8.23
(d, J = 9.0 Hz, 2H, H-2Ph,6Ph), 7.95 (t, J = 7.8 Hz, 1H, H-8), 7.87 (d, J =
9.0 Hz, 2H, H-3Ph,5Ph), 7.82 (t, J = 7.8 Hz, 1H, H-9), 4.82 (q, J =
7.1 Hz, 1H, SCH), 1.73 (d, J = 7.1 Hz, 3H, SCHCH3); LC-MS m/z: 395
[M + H]+. Anal. calcd. for C18H14N6O3S: C, 54.82; H, 3.58; N, 21.31;
S, 8.13. Found: C, 54.71; H, 3.52; N, 21.36; S, 8.18.
Compound 7.1
IR (cm–1): 3303, 3058, 2932, 1637, 1535, 1515, 1479, 1457, 1395,
1
1333,1266, 1200, 1002, 902, 782, 768, 738, 715, 695, 644; H-
NMR (500 MHz) d: 9.50 (s, 1H, H-5), 8.37 (d, J = 7.9 Hz, 1H, H-10),
8.04 (d, J = 7.8 Hz, 1H, H-7), 7.92 (t, J = 8.0 Hz, 1H, H-8), 7.79 (t, J =
7.8 Hz, 1H, H-9), 7.40 (m, 1H, NH), 7.24 (m, 5H, H-Ph), 3.32 (m, 2H,
SCH2), 2.48 (t, J = 3.8 Hz, 2H, SCH2CH2), 2.03 (q, J = 7.5 Hz, 2H,
S(CH2)2CH2); LC-MS m/z: 378 [M + H]+, 380, 381; EI-MS m/z (I,%): 378
(2.1), 377 (9.9) [M]+9, 270 (4.3), 257 (1.6), 243 (10.1), 231 (5.2), 230
(11.7), 229 (100.0), 216 (12.2), 215 (3.1), 203 (7.1), 202 (6.0), 197
(4.6), 176 (4.5), 171 (3.2), 149 (12), 148 (5.1), 130 (4.0), 129 (13.6),
107 (6.1), 106 (36.1), 102 (93.1), 92 (7.8), 91 (72.9), 85 (4.4), 83 (6.6),
Compound 5.11
IR (cm–1): 3307, 3269, 3197, 3062, 2972, 2931, 2310, 1687, 1610,
1550, 1516, 1490, 1477, 1453, 1392, 1375, 1343, 1300, 1251,
1174, 1087, 1010, 898, 831, 808, 773, 717, 659; 1H-NMR
i 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2009, 342, 651–662
2-Thio-[1,2,4]triazolo[1,5-c]quinazolines
661
79 (4.9), 77 (5.6), 69 (11.9), 59 (5.4). Anal. calcd. for C20H19N5OS: C,
62.64; H, 5.07; N, 18.55; S, 8.49. Found: C, 62.73; H, 4.85; N, 18.53;
S, 8.69.
LC-MS m/z: 442 [M + H]+, 444; EI-MS m/z (I,%): 443 (10.3), 442 (2.4)
[M]+, 441 (9.9), 271 (14.5), 270 (4.5), 243 (4.2), 231 (5.3), 230 (12.2),
229 (100.0), 216 (12.2), 215 (9.7), 204 (5.2), 203 (47.7), 202 (19.2),
197 (8.0), 184 96.8), 173 (55.0), 172 (18.9), 171 (59.0), 170 (18.8),
157 (5.9), 156 (5.0), 146 (5.0), 145 (14.9), 143 (6.4), 130 (9.9), 129
(44.6), 117 (3.9), 107 (6.1), 103 (6.4), 102 (33.2), 92 (13.7), 91 (27.6),
90 (10.8), 88 (5.7). Anal. calcd. for C19H16BrN5OS: C, 51.59; H, 3.65;
N, 15.83; S, 7.25. Found: C, 51.65; H, 3.69; N, 15.74; S, 7.30.
Compound 7.2
IR (cm–1): 3323, 3060, 2966, 2918, 1665, 1621, 1599, 1515, 1478,
1442, 1393, 1329, 1265, 1183, 1035, 963, 901, 782, 765, 744, 714,
682, 610; 1H-NMR (500 MHz) d: 9.90 (br.s, 1H, NH), 9.45 (s, 1H, H-
5), 8.34 (d, J = 7.8 Hz, 1H, H-10), 8.02 (d, J = 7.8 Hz, 1H, H-7), 7.90 (t,
J = 7.8 Hz, 1H, H-8), 7.76 (t, J = 7.8 Hz, 1H, H-9), 7.75 (d, J = 7.8 Hz,
2H, H-2Ph,6Ph), 7.25 (t, J = 7.8 Hz, 2H, H-3Ph,5Ph), 6.98 (t, J = 7.8 Hz,
1H, H-4Ph), 3.35 (t, J = 6.9 Hz, 2H, SCH2), 2.51 (t, J = 7.2 Hz, 2H,
SCH2CH2), 2.09 (q, J = 7.2 Hz, 2H, S(CH2)2CH2); LC-MS m/z: 364 [M +
H]+, 366. Anal. calcd. for C19H17N5OS: C, 62.79; H, 4.71; N, 19.27; S,
8.82. Found: C, 62.76; H, 4.61; N, 19.27; S, 8.71.
Compound 7.7
IR (cm–1): 3296, 3053, 2909, 2310, 1659, 1602, 1602, 1517, 1478,
1446, 1393, 1329, 1256, 3649, 1112, 960, 902, 783, 783, 769, 715,
694, 661, 643; 1H-NMR (500 MHz) d: 10.26 (br.s, 1H, NH), 9.48 (s,
1H, H-5), 8.34 (d, J = 8.0 Hz, 1H, H-10), 8.07 (s, 1H, H-2Ph), 8.03 (d, J
= 8.0 Hz, 1H, H-7), 7.91 (t, J = 7.8 Hz, 1H, H-8), 7.76 (t, J = 7.8 Hz,
1H, H-9), 7.73 (d, J = 8.0 Hz, 1H, H-6Ph), 7.50 (t, J = 8.0 Hz, 1H, H-5Ph),
7.35 (d, J = 7.8 Hz, 1H, H-4Ph), 3.38 (t, J = 6.8 Hz, 2H, SCH2), 2.56 (t, J
= 6.8 Hz, 2H, SCH2CH2), 2.13 (q, J = 6.8 Hz, 2H, S(CH2)2CH2); LC-MS
m/z: 432 [M + H]+, 435. Anal. calcd. for C20H16F3N5OS: C, 55.68; H,
3.74; N, 16.23; S, 7.43. Found: C, 55.77; H, 3.87; N, 16.27; S, 7.41.
Compound 7.3
IR (cm–1): 3295, 3053, 2972, 2934, 1662, 1623, 1604, 1519, 1478,
1454, 1393, 1324, 1287, 1256, 1181, 1104, 903, 769, 745, 717,
966, 692,645;1H-NMR (500 MHz) d: 9.50 (s, 1H, H-5), 9.31 (br.s, 1H,
NH), 8.37 (d, J = 7.8 Hz, 1H, H-10), 8.04 (d, J = 7.8 Hz, 1H, H-7), 7.92
(t, J = 7.8 Hz, 1H, H-8), 7.78 (t, J = 7.8 Hz, 1H, H-9), 7.36 (d, J =
7.6 Hz, 1H, H-6Ph), 7.05 (d, J = 7.6 Hz, 2H, H-3Ph,5Ph), 7.17 (d, J =
7.6 Hz, 1H, H-4Ph), 3.36 (t, J = 7.0 Hz, 2H, SCH2), 3.32 (s, 3H, CH3),
2.53 (t, J = 7.2 Hz, 2H, SCH2CH2), 2.11 (m, 2H, S(CH2)2CH2); LC-MS
m/z: 378 [M + H]+, 380. Anal. calcd. for C20H19N5OS: C, 62.64; H,
5.07; N, 18.55; S, 8.49. Found: C, 62.71; H, 4.89; N, 18.56; S, 8.55.
Biological assays
Bioluminescence inhibition test
The marine luminescent bacteria Photobacterium leiognathi strain
Sh1, isolated from the Azov Sea Shrimp, were used for the biolu-
minescence analysis [13]. Bacteria were cultivated on a nutrient
environment containing (g/L): pepton – 5, yeast extract – 1.5,
meat extract – 1.5, sodium chloride – 30, pH = 7.4. In the acute
action test (inhibiting luminescence of bacteria), bacteria were
diluted with the 3% sodium chloride solution up to a concentra-
tion of 105 cells/mL. 5–50 lg/mL of the studied substances sus-
pended in DMSO were mixed with 1 mL of the diluted bacterial
suspension. Vials were incubating for 10 min at 258C, then, the
intensity of bioluminescence was measured in percent (%) rela-
tive to the controls, which were prepared without the studied
compounds. In the chronic action test (inhibiting growth and
luminescence of bacteria), growth medium was added for poten-
tial breeding in a ratio of 1:50 and the mix was incubated for
16–18 h at 308C, whereupon the intensity of bioluminescence
was measured the same way as in acute action testing. Tetracy-
cline was used as a reference. The bacterial luminescence was
measured with a Bioluminometer BLM-8801 («Science», Kra-
snoyarsk, Russia).
Compound 7.4
IR (cm–1): 3057, 2973, 2927, 1621, 1721, 1595, 1515, 1477, 1453,
1
1370, 1240, 1175, 1031, 899, 773, 747, 714, 698, 639; H-NMR
(400 MHz) d: 9.50 (s, 1H, H-5), 9.12 (br.s, 1H, NH), 8.37 (d, J =
7.8 Hz, 1H, H-10), 8.04 (d, J = 7.8 Hz, 1H, H-7), 7.93 (t, J = 7.6 Hz,
2H, H-8, H-5Ph), 7.79 (t, J = 7.6 Hz, 1H, H-9), 7.02 (m, 2H, H-3Ph,6Ph),
6.88 (t, J = 7.6 Hz, 1H, H-4Ph), 3.78 (s, 3H, OCH3), 3.36 (t, J = 6.8 Hz,
2H, SCH2), 2.59 (t, J = 6.8 Hz, 2H, SCH2CH2), 2.10 (q, J = 6.8 Hz, 2H,
S(CH2)2CH2); LC-MS m/z: 394 [M + H]+. Anal. calcd. for C20H16N5O2S:
C, 61.05; H, 4.87; N, 17.80; S, 8.15. Found: C, 61.12; H, 4.97; N,
17.74; S, 8.25.
Compound 7.5
IR (cm–1): 3294, 2965, 2931, 2833, 1651, 1624, 1593, 1523, 1478,
1396, 1303, 1261, 1218, 1178, 1140, 1029, 971, 902, 804, 782,
1
718, 646; H-NMR (500 MHz) d: 9.49 (s, 1H, H-5), 9.27 (br.s, 1H,
Antimicrobial and antifungal test
NH), 8.36 (d, J = 8.0 Hz, 1H, H-10), 8.1 (s, 1H, H-3Ph), 8.04 (d, J =
8.0 Hz, 1H, H-7), 7.93 (t, J = 7.8 Hz, 1H, H-8), 7.79 (t, J = 7.8 Hz, 1H,
H-9), 7.07 (d, J = 8.8 Hz, 1H, H-3Ph), 7.00 (d, J = 8.8 Hz, 1H, H-5Ph),
3.78 (s, 3H, OCH3), 3.35 (t, J = 6.8 Hz, 2H, SCH2), 2.61 (t, J = 6.8 Hz,
2H, SCH2CH2), 2.09 (q, J = 6.8 Hz, 2H, S(CH2)2CH2); LC-MS m/z: 428
[M + H]+, 430, 432. Anal. calcd. for C20H18ClN5O2S: C, 56.14; H,
4.24; N, 16.37; S, 7.49. Found: C, 56.19; H, 4.32; N, 16.43; S, 7.35.
The investigation of antimicrobial and antifungal activity of
amides 4–7 was carried out with the stiff plate agar diffusion
method against Escherichia coli, Staphylococcus aureus, Mycobacte-
rium luteum, Candida tenuis, and Aspergillus niger. The amount of
microbial cells was 109 c.f.u./mL. Incubation period of bacteria
was 24 h at 358C, yeast – 48 to 72 h at 28–308C. Antibiotics vanco-
micin, oxacillin, nystatin were used as standards. The bacterial
cultures, the standards and the obtained substances were
streaked across grooves in 5 mg/mL concentration, and then
allowed to diffuse in the agar nutrient plate. The antimicrobial
effect and degree of activity of the tested compounds were eval-
uated by measuring of the zone diameters (not sensitive: 11–
15 mm; sensitive: 16–25 mm; highly sensitive >25 mm). The
results were compared with well-known drug standards vanco-
micin, nystatin, and oxacillin. All experiments were repeated
three times.
Compound 7.6
IR (cm–1): 3304, 3057, 1658, 1621, 1588, 1513, 1478, 1454, 1391,
1326, 1264, 1181, 1105, 1070, 1007, 971, 901, 813, 782, 766, 714,
643; 1H-NMR (500 MHz) d: 10.05 (br.s, 1H, NH), 9.48 (s, 1H, H-5),
8.36 (d, J = 7.8 Hz, 1H, H-10), 8.04 (d, J = 7.8 Hz, 1H, H-7), 7.93 (t, J =
7.8 Hz, 1H, H-8), 7.78 (t, J = 7.8 Hz, 1H, H-9), 7.54 (d, J = 8.0 Hz, 2H,
H-2Ph,6Ph), 7.43 (d, J = 7.6 Hz, 2H, H-3Ph,5Ph), 3.36 (t, J = 6.8 Hz, 2H,
SCH2), 2.50 (m, 2H, SCH2CH2), 2.11 (q, J = 6.8 Hz, 2H, S(CH2)2CH2);
i 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

662
L. N. Antipenko et al.
Arch. Pharm. Chem. Life Sci. 2009, 342, 651–662
The authors gratefully acknowledge “Enamine Ltd.” (Kiev, Ukraine) for
financial support of this work.
[7] A. C. Pasqualotto, D. W. Denning, J. Antimicrob. Chemother.
2008, 61, 19–30.
[8] M. A. Likhate, P. S. Fernandes, J. Indian Chem. Soc. 1990, 67
(10), 862–863.
The authors have declared no conflict of interest.
[9] S. S. Ibrahim, A. M. Abdel-Halim, Y. Gabr, S. El-Edfawy, R.
M. Abdel-Rahman, J. Chem. Res. (M) 1997, 5, 1041–1063.
[10] R. El-Sayed, A. A. F. Wasfy, A. A. Aly, J. Oil Soap Cosmetics
2004, 53, 247–251.
References
[11] R. El-Sayed, A. A. F. Wasfy, J. Chin. Chem. Soc. 2005, 52, 129–
[1] F. A. Barile, Introduction to in vitro cytotoxicology, Mecha-
nisms and Methos, CRC Press, Inc., New York 1994.
135.
[12] R. El-Sayed, A. A. F. Wasfy, A. A. Aly, J. Heterocycl. Chem.
2005, 42, 125–130.
[2] S. Girott, E. N. Ferri, M. G. Fumo, E. Maiolini, Anal. Chim.
Acta 2008, 608 (1), 2–29.
[13] L. N. Antipenko, A. V. Karpenko, S. I. Kovalenko, A. M. Kat-
sev, E. Komarovska-Porokhnyavets, V. Norikov, A. Cheko-
tilo, Chem. Pharm. Bull. 2009, 57, 580–585.
[3] M. J. Struelens, O. Denis, H. Rodriguez-Villalobos, M. Hal-
lin, Rev. Med. Brux. 2007, 28 (4), 381–384.
[4] E. D. Brown, G. D. Wright, Chem. Rev. 2005, 105, 759–774.
[5] A. Espinel-Ingroff, Rev. Iberoam. Micol. 2009, 26 (1), 15–22.
[14] P. Wyatt, S. Warren, Organic synthesis: strategy and control,
John Wiley & Sons Ltd., Chichester 2007.
[6] N. N. Klimko, A. V. Veselov, Clinicheskaya Microbiologiya i
Antimicrobnaya Chimioterapiya 2003, 5 (4), 342–353 (Russ.
Ed.); N. N. Klimko, A. V. Veselov, CMAC 2003, 5 (4), 342–353
(Engl. Transl.).
[15] A. V. Karpenko, S. I. Kovalenko, S. V. Shishkina, O. V. Shish-
kin, Monatsh. Chem. 2006, 137, 1543–1549.
[16] E. J. Calabrese, R. B. Blain, Environ. Pollut. 2009, 157, 42–48.
i 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com