Synthesis and Characterization of Novel N-(Phenyl, Benzyl, Hetaryl)-2-([1,2,4]Triazolo[1,5-c]Quinazolin-2-ylthio)Acetamides by Spectral Data, Antimicrobial Activity, Molecular Docking and QSAR Studies

Article abstract of DOI:10.1002/jhet.2702

Enduring the novel effective antimicrobial agents search, N-(phenyl, benzyl, hetaryl)-2-([1,2,4]triazolo[1,5-c]quinazolin-2-ylthio)acetamides were synthesized, evaluated for structure (LC-MS, IR, ¹H-NMR spectra and elemental analysis), and inve

Full text of DOI:10.1002/jhet.2702

Month 2016
Synthesis and Characterization of Novel N-(Phenyl, Benzyl, Hetaryl)-2-
(
[1,2,4]Triazolo[1,5-c]Quinazolin-2-ylthio)Acetamides by Spectral Data,
Antimicrobial Activity, Molecular Docking and QSAR Studies
a
a
a
b
Lyudmyla M. Antypenko, * Sergiy I. Kovalenko, Tetyana S. Los', and Oksana L. Rebec'
a
Organic and Bioorganic Chemistry Department, Zaporizhzhya State Medical University, 26, Mayakovsky Ave.,
Zaporizhzhya, 69035, Ukraine
Bacterial Laboratory, Zaporizhzhya Regional Hospital, 10, Orehovskoe shosse, Zaporizhzhya, 69050, Ukraine
b
*
E-mail: antypenkol@gmail.com
Additional Supporting Information may be found in the online version of this article.
Received March 4, 2016
DOI 10.1002/jhet.2702
Published online 00 Month 2016 in Wiley Online Library (wileyonlinelibrary.com).
Enduring the novel effective antimicrobial agents search, N-(phenyl, benzyl, hetaryl)-2-([1,2,4]triazolo
1,5-c]quinazolin-2-ylthio)acetamides were synthesized, evaluated for structure (LC-MS, IR, H-NMR spec-
1
[
tra and elemental analysis), and investigated for antibacterial activity against Staphylococcus aureus, Entero-
coccus faecalis, Enterobacter aerogenes, Cronobacter sakazaki, Pseudomonas aeruginosa, Escherichia coli,
and Klebsiella pneumonia, and antifungal – against Candida albicans. N-(4-Fluorophenyl)-2-([1,2,4]triazolo
[
1,5-c]quinazolin-2-ylthio)acetamide 3e had the best minimum inhibition zones against S. aureus and E.
faecalis and 3-{[([1,2,4]triazolo[1,5-c]quinazolin-2-ylthio)acetyl]amino}benzoic acid 3k – against E. coli,
still in lower concentration, than references. By the means of in silico molecular docking into the active sites
of E. faecalis dihydrofolate reductase and Enterobacter cloacae MyrA, the possible activity mechanism was
suggested. The quantitative structure–activity relationship model for antimicrobial activity prediction was
calculated.
J. Heterocyclic Chem., 00, 00 (2016).
INTRODUCTION
Considering the most active antimicrobial and antifungal
compounds against S. aureus, P. aeruginosa, K. pneumo-
nia, and C. albicans, unsubstituted, 2-methyl-, and 2-
phenylquinazolin-4(3H)-thiones, C appeared to be the
strongest (Fig. 1) [4], and 1-(2,5-dimethoxyphenyl)-2-
([1,2,4]triazolo[1,5-c]quinazolin-2-ylthio)ethanone was
effective against Escherichia coli, S. aureus, Cystopteris
tenius and Aspergillus niger [5]. The 2-([1,2,4]triazolo
[1,5-c]quinazolin-2-ylthio)-N-butylpropanamide, N-(2-
methoxyphenyl)-propanamide, and N,N-diethylacetamide
D [6] also inhibited growth of A niger. Analyzing the liter-
ature data about other triazole and quinazoline substituted
amides as antimicrobials, investigation of (Z)-N-(4-(3-
(2,4-dichlorophenyl)-3-oxo-2-(1H-1,2,4-triazolo-1-yl)
prop-1-enyl)phenyl)benzamides, E [7] showed that they
inhibited the growth of fungi Pellicularia sasakii,
Gibberella zeae, Fusarium oxysporum, Cytospora
mandshurica, Phytophthora infestans and bacteria
Ralstonia solanacearum. As well Metkonazol and
Triadimefon [8] also had antifungal properties and exhibit
According to the latest paper of Spellberg and Shlaes [1]
about antibiotic resistance among the top areas of unmet
medical treatment are extreme drug-resistant (XDR) and
pan drug-resistant (PDR) Gram negative bacilli infection,
common community-onset infections such as urinary tract
infections and intra-abdominal infections caused by gram
negative bacilli to all oral options, XDR/PDR tuberculosis,
bloodstream, and bone infections caused by MRSA, and
XDR/PDR gonorrhea. Thus, it is of undoubted interest, to
synthesize and investigate for antimicrobial activity the
novel antimicrobial agents as continuation of novel deriva-
tives of [1,2,4]triazolo[1,5-c]quinazoline search, which
were already proven to have high antifungal activity
against Candida ablicans, namely ([1,2,4]triazolo[1,5-c]
quinazolin-2-ylthio)acetic and propionic acids, A [2], and
antimicrobial activity against Staphylococcus aureus –
potassium 2-heteroaryl-[1,2,4]triazolo[1,5-c]quinazoline-
5
-thiolates, B [3] (Fig. 1).
©
2016 Wiley Periodicals, Inc.

L. M. Antypenko, S. I. Kovalenko, T. S. Los' and O. L. Rebec'
Vol 000
Figure 1. Structures of antimicrobial representatives of quinazolines, 1,2,4-triazoles and [1,2,4]triazolo[1,5-c]quinazolines.
antimicrobial activity against Paralepetopsis sasakii, F.
oxysporum, Corylus mandshurica, and Phytophthora
infestans.
Other starting materials and solvents were obtained from
commercially available sources and used without
additional purification.
Hence, it was decided to extend the series of amides
among [1,2,4]triazolo[1,5-c]quinazolin-2-ylthio-derivatives
for synthesis and screening for antimicrobial properties
against the most common microbial pathogens by drug-like
modeling with subsequent molecular docking studies and
quantitative structure–activity relationship (QSAR)
analysis.
Examples of 1d, 2c, 3b spectra are given in the
Appendix S1.
General procedure for the synthesis of 2-([1,2,4]triazolo
[1,5-c]quinazolin-2-ylsulfanyl)acetamides.
To solution of
corresponding halogenoacetamide (0.005 mol) in 10mL
of propan-2-ol the solution of potassium [1,2,4]triazolo
[1,5-c]quinazolin-5-thiole (0.005mol) in 10mL of water
was added. The mixture was refluxed for 2h and then
cooled down. The precipitate was filtered, washed with
water, dried and recrystallized from propan-2-ol.
EXPERIMENTAL
N-(2-chlorobenzyl)-2-([1,2,4]triazolo[1,5-c]quinazolin-2-ylthio)
acetamide (1a). Yellow solid. Yield: 31.0ꢀ, mp. 150–
152°C. IR (cm ) 3391, 3261, 3202, 3056, 2949, 2918,
Chemistry. Melting points were determined in open
capillary tubes in a Thiele’s apparatus and were
uncorrected. The elemental analyses (C, H, N, S) were
performed using the ELEMENTAR vario EL Cube
analyzer (Hanau, Germany). Analyses were indicated by
the symbols of the elements or functions within ±0.3ꢀ of
À1
2867, 1693, 1622, 1605, 1553, 1518, 1481, 1455, 1400,
1385, 1375, 1359, 1308, 1258, 1212, 1161, 1141, 1107,
1072, 1054, 967, 909, 834, 785, 768, 741, 717, 694, 675,
1
621. H NMR δ (ppm) 9.36 (s, 1H, H-5), 8.65 (br. s, 1H,
À1
the theoretical values. IR spectra (4000–600 cm ) were
recorded on a Bruker ALPHA FT-IR spectrometer
NH), 8.40 (d, J =7.8 Hz, 1H, H-10), 8.02 (d, J =8.0 Hz,
1H, H-7), 7.90 (t, J =7.7 Hz, 1H, H-8), 7.77 (t, J =7.5 Hz,
1H, H-9), 7.35 (d, J= 7.6 Hz, 1H, Ph-3), 7.31 (d,
J = 7.6 Hz, 1H, Ph-6), 7.17–7.12 (m, J = 7.6 Hz, 2H, Ph-
(
Ettlingen, Germany) using a module for measuring
1
attenuated total reflection. H NMR spectra (400MHz)
were recorded on a Varian-Mercury 400 spectrometer
4,5), 4.39 (d, J =5.6 Hz, 2H, HNCH ), 4.08 (s, 2H,
2
+
(Palo Alto, CA) with SiMe4 as internal standard in
SCH ). LC-MS m/z = 384 [M +H] . Anal. Calcd for
2
DMSO-d +CCl solution. LC-MS were recorded using
C H ClN OS: S, 56.32; H,3.68; N, 18.24; S, 8.35.
6
4
18 14
5
chromatography/mass spectrometric system which
consisted of high-performed liquid chromatograph
Found: S, 56.33; H, 3.70; N, 18.26; S, 8.36.
N-(3-chlorobenzyl)-2-([1,2,4]triazolo[1,5-c]quinazolin-2-ylthio)
“
Agi1ent 1100 Series” equipped with diode-matrix and
mass-selective detector “Agi1ent LC/MSD SL”
atmospheric pressure chemical ionization – APCI (Palo
acetamide (1b).
Light brown solid. Yield: 48.5ꢀ, mp.
À1
265–267°C. IR (cm ) 3286, 3053, 2923, 2852, 1698,
1670, 1620, 1599, 1575, 1539, 1517, 1494, 1477, 1454,
1428, 1397, 1385, 1357, 1339, 1313, 1285, 1249, 1203,
1156, 1127, 1105, 1078, 1039, 1017, 977, 939, 904, 863,
(
Alto, CA)). The purity of all obtained compounds was
checked by H NMR and LC–MS.
1
1
Potassium [1,2,4]triazolo[1,5-c]quinazolin-2-thiole
1
848, 774, 743, 717, 700, 670. H NMR δ (ppm) 9.34 (s,
was synthesized according to the reported procedure [9].
1H, H-5), 8.67 (br. s, 1H, NH), 8.58 (d, J = 7.2Hz, 1H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
N-(Phenyl, Benzyl, Hetaryl)-2-([1,2,4]Triazolo[1,5-c]Quinazolin-2-ylthio)Acet-
amides Antimicrobial Activity
À1
Ph-6), 8.39 (d, J =7.7 Hz, 1H, H-10), 8.02 (d, J= 8.1 Hz,
159°C. IR (cm ) 3834, 3745, 3617, 3315, 2917, 1756,
1670, 1616, 1551, 1522, 1477, 1454, 1388, 1311, 1258,
1203, 1100, 1076, 1017, 979, 938, 905, 846, 774, 752,
1
1
H, H-7), 7.88 (t, J= 7.4Hz, 1H, H-8), 7.78 (t, J= 7.5 Hz,
H, H-9), 7.27–7.10 (m, 4H, Ph-2,4), 4.36–4.28 (m, 2H,
1
NHCH ), 4.05 (s, 2H, SCH ). LC-MS m/z =384 [M
714, 638. H NMR δ (ppm) 9.35 (s, 1H, H-5), 8.61 (br.
2
2
+
+
H] . Anal. Calcd for C H ClN OS: S, 56.32; H, 3.68;
s, 1H, NH), 8.47 (s, 1H, H-10), 8.02 (d, J = 8.1 Hz, 1H,
H-7), 7.90 (t, J = 7.0 Hz, 1H, H-8), 7.77 (t, J = 7.6Hz, 1H,
H-9), 7.19 (d, J =5.9 Hz, 2H, Ph-3,6), 7.01 (t, J =7.7 Hz,
1
8
14
5
N, 18.24; S, 8.35. Found: S, 56.34; H, 3.67; N. 18.25; S,
.33.
8
N-(4-chlorobenzyl)-2-([1,2,4]triazolo[1,5-c]quinazolin-2-ylthio)
2H, Ph-4,5), 4.36 (d, J= 5.7 Hz, 2H, HNCH ), 4.06 (s,
2
+
acetamide (1c).
89–190°C. IR (cm ) 3315, 3055, 2918, 2850, 1669,
Light brown solid. Yield: 35.0ꢀ, mp.
2H, SCH ). LC-MS m/z = 368 [M + H] . Anal. Calcd for
2
À1
1
1
1
1
7
C H FN OS: S, 58.84; H, 3.84; N, 19.06; S, 8.73.
18
14
5
621, 1603, 1553, 1517, 1491, 1476, 1454, 1397, 1383,
374, 1358, 1310, 1297, 1257, 1210, 1191, 1177, 1104,
088, 1050, 1014, 962, 938, 904, 879, 833, 814, 800,
Found: S, 58.84; H, 3.86; N, 19.08; S, 8.73.
N-(3-fluorobenzyl)-2-([1,2,4]triazolo[1,5-c]quinazolin-2-ylthio)
acetamide (1g).
Light brown solid. Yield: 40.3ꢀ, mp.
1
À1
83, 717, 668, 645, 622. H NMR δ (ppm) 9.36 (s, 1H,
171–173°C. IR (cm ) 3327, 3290, 3064, 2909, 1668,
1620, 1604, 1591, 1551, 1516, 1479, 1453, 1397, 1385,
1360, 1317, 1265, 1252, 1204, 1137, 1105, 1075, 1024,
1005, 981, 950, 929, 904, 859, 778, 743, 718, 683, 669,
H-5), 8.64 (br. s, 1H, NH), 8.37 (d, J =7.8 Hz, 1H, H-10),
.02 (d, J = 8.1Hz, 1H, H-7), 7.89 (t, J =7.5Hz, 1H, H-
), 7.77 (t, J = 7.4 Hz, 1H, H-9), 7.25 (d, J = 8.1 Hz, 2H,
8
8
1
Ph-3,5), 7.20 (d, J = 8.1Hz, 2H, Ph-2,6), 4.31 (d,
J =5.7 Hz, 2H, HNCH ), 4.04 (s, 2H, SCH ). LC-MS m/
644, 617. H NMR δ (ppm) 9.34 (s, 1H, H-5), 8.66 (br.
2
2
s, 1H, NH), 8.40 (d, J = 8.2 Hz, 1H, H-10), 8.02 (d,
J = 8.1 Hz, 1H, H-7), 7.89 (t, J = 7.3 Hz, 1H, H-8), 7.77 (t,
J = 7.4 Hz, 1H, H-9), 7.25–7.20 (m, 1H, Ph-5), 7.06 (d,
J = 7.6 Hz, 1H, Ph-4), 7.01 (d, J =9.3 Hz, 1H, Ph-5), 6.88
+
z =384 [M + H] . Anal. Calcd for C H ClN OS: S,
1
8
14
5
5
3
6.32; H, 3.68; N, 18.24; S, 8.35. Found: S, 56.33; H,
.71; N, 18.25; S, 8.37.
N-(2-bromobenzyl)-2-([1,2,4]triazolo[1,5-c]quinazolin-2-
(s, 1H, Ph-2), 4.34 (d, J= 5.8 Hz, 2H, NHCH ), 4.05 (s,
2
+
ylthio)acetamide (1d).
47–145°C. IR (cm ) 3299, 3056, 2918, 1681, 1666,
White solid. Yield: 45.5ꢀ, mp.
2H, SCH ). LC-MS m/z = 368 [M + H] . Anal. Calcd for
2
À1
1
1
1
1
7
9
C H FN OS: S, 58.84; H, 3.84; N, 19.06; S, 8.73.
18
14
5
623, 1607, 1564, 1555, 1537, 1518, 1478, 1455, 1440,
422, 1400, 1388, 1359, 1326, 1313, 1269, 1213, 1195,
130, 1106, 1069, 1046, 1028, 948, 931, 907, 782, 768,
Found: S, 58.86; H, 3.85; N, 19.08; S, 8.74.
N-(4-fluorobenzyl)-2-([1,2,4]triazolo[1,5-c]quinazolin-2-ylthio)
acetamide (1h).
Light brown solid. Yield: 49.5ꢀ, mp.
1
À1
53, 716, 696, 673, 660, 647, 614. H NMR δ (ppm)
186–188°C. IR (cm ) 3321, 3048, 2920, 2850, 1667,
1620, 1603, 1547, 1506, 1476, 1453, 1445, 1413, 1395,
1384, 1357, 1315, 1263, 1254, 1226, 1195, 1152, 1104,
1092, 1016, 982, 963, 937, 903, 878, 849, 818, 805, 781,
.37 (s, 1H, H-5), 8.62 (br. s, 1H, NH), 8.41 (d,
J =7.9 Hz, 1H, H-10), 8.03 (d, J =8.1Hz, 1H, H-7), 7.90
t, J = 7.7Hz, 1H, H-8), 7.78 (t, J = 7.5Hz, 1H, H-9), 7.48
d, J = 7.7Hz, 1H, Ph-3), 7.34 (d, J = 7.3Hz, 1H, Ph-6),
(
(
7
5
1
761, 718, 643. H NMR δ (ppm) 9.36 (s, 1H, H-5), 8.64
.19 (t, J = 7.1Hz, 1H, Ph-4), 7.10 (t, J = 7.5Hz, 1H, Ph-
), 4.37 (d, J = 5.7 Hz, 2H, HNCH ), 4.09 (s, 2H, SCH ).
(br. s, 1H, NH), 8.37 (d, J = 7.8 Hz, 1H, H-10), 8.02 (d,
J = 8.1 Hz, 1H, H-7), 7.89 (t, J = 7.5 Hz, 1H, H-8), 7.77 (t,
J = 7.4 Hz, 1H, H-9), 7.25 (d, J = 8.1 Hz, 2H, Ph-3,5),
6.35 (d, J = 8.1 Hz, 2H, Ph-2,6), 4.31 (d, J =5.7Hz, 2H,
HNCH ), 4.04 (s, 2H, SCH ). LC-MS m/z = 368 [M
2
2
+
LC-MS m/z = 429 [M + H] . Anal. Calcd for
C H BrN OS: S, 50.48; H, 3.29; N, 16.35; S, 7.49.
18
14
5
Found: S, 50.50; H, 3.28; N, 16.36; S, 7.55.
N-(4-bromobenzyl)-2-([1,2,4]triazolo[1,5-c]quinazolin-2-ylthio)
2
2
+
+
H] . Anal. Calcd for C H FN OS: S, 58.84; H, 3.84;
18 14 5
acetamide (1e).
41–143°C. IR (cm ) 3748, 3321, 2924, 2851, 1672,
Light brown solid. Yield: 75.0ꢀ, mp.
N, 19.06; S, 8.73. Found: S, 56.83; H, 3.85; N, 19.08; S,
.71.
À1
1
1
1
1
1
8
619, 1603, 1531, 1517, 1487, 1475, 1454, 1395, 1382,
373, 1310, 1296, 1258, 1192, 1176, 1103, 1069, 1051,
N-(2-(fluoromethyl)benzyl)-2-([1,2,4]triazolo[1,5-c]quinazolin-
2
1
-ylthio)acetamide (1i). Yellow solid. Yield: 43.5ꢀ, mp.
43–145°C. IR (cm ) 3276, 3066, 2931, 2856, 1734,
1
À1
011, 904, 798, 783, 718, 627. H NMR δ (ppm) 9.36 (s,
H, H-5), 8.64 (br. s, 1H, NH), 8.37 (d, J = 7.8 Hz, 1H,
1717, 1683, 1653, 1635, 1624, 1606, 1576, 1558, 1550,
1533, 1520, 1508, 1498, 1478, 1456, 1436, 1398, 1372,
1357, 1310, 1265, 1246, 1220, 1192, 1162, 1116, 1071,
1058, 1033, 981, 960, 934, 900, 886, 868, 804, 767, 717,
H-10), 8.02 (d, J= 8.1Hz, 1H, H-7), 7.89 (t, J= 7.5 Hz,
H, H-8), 7.77 (t, J= 7.4Hz, 1H, H-9), 7.25 (d,
J =8.1 Hz, 2H, Ph-3,5), 7.20 (d, J= 8.1Hz, 2H, Ph-2,6),
.31 (d, J= 5.7Hz, 2H, HNCH ), 4.04 (s, 2H, SCH ).
1
1
4
673, 644, 626. H NMR δ (ppm) 9.37 (s, 1H, H-5), 8.62
2
2
+
LC-MS m/z = 429 [M + H] . Anal. Calcd for
(br. s, 1H, NH), 8.41 (d, J = 7.9 Hz, 1H, H-10), 8.03 (d,
J = 8.1 Hz, 1H, H-7), 7.90 (t, J = 7.7 Hz, 1H, H-8), 7.78 (t,
J = 7.5 Hz, 1H, H-9), 7.48 (d, J = 7.7 Hz, 1H, Ph-3), 7.34
(d, J= 7.3 Hz, 1H, Ph-6), 7.19 (t, J = 7.1 Hz, 1H, Ph-4),
7.10 (t, J = 7.5 Hz, 1H, Ph-5), 4.37 (d, J = 5.7Hz, 2H,
C H BrN OS: S, 50.48; H, 3.29; N, 16.35; S, 7.49.
18
14
5
Found: S, 50.50; H, 3.30; N. 16.37; S, 7.50.
N-(2-fluorobenzyl)-2-([1,2,4]triazolo[1,5-c]quinazolin-2-ylthio)
acetamide (1f).
Orange solid. Yield: 45.5ꢀ, mp. 157–
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

L. M. Antypenko, S. I. Kovalenko, T. S. Los' and O. L. Rebec'
Vol 000
+
HNCH ), 4.09 (s, 2H, SCH ). LC-MS m/z =418 [M+ H] .
1162, 1153, 1107, 1096, 1052, 993, 966, 934, 907, 871,
818, 761, 752, 737, 718, 658, 618. H NMR δ (ppm)
2
2
1
Anal. Calcd for C H F N OS: S, 54.67; H, 3.38; N,
1
9 14 3 5
1
6.78; S, 7.68. Found: S, 54.65; H, 3.40; N, 16.80; S, 7.69.
N-(4-(fluoromethyl)benzyl)-2-([1,2,4]triazolo[1,5-c]quinazolin-
12.76 (br. s, 1H, NH), 9.36 (s, 1H, H-5), 8.39 (d,
J = 7.9 Hz, 1H, H-10), 8.01 (d, J = 8.1 Hz, 1H, H-7), 7.88
(t, J= 7.6 Hz, 1H, H-8), 7.76 (t, J = 7.4 Hz, 1H, H-9), 4.34
(s, 2H, SCH ), 2.83 (t, J= 6.7 Hz, 2H, CH C H ), 1.23 (s,
2-ylthio)acetamide (1j). Yellow solid. Yield: 50.3ꢀ, mp.
À1
1
3
1
1
1
7
8
78–180°C. IR (cm ) 3868, 3856, 3746, 3736, 3724,
610, 3336, 3310, 3064, 2924, 2854, 1711, 1690, 1673,
650, 1621, 1564, 1551, 1535, 1515, 1502, 1479, 1453,
418, 1397, 1386, 1323, 1266, 1254, 1212, 1193, 1158,
107, 1066, 1018, 982, 938, 905, 817, 783, 776, 753,
2
2 3 7
3H, CH ), 1.01–0.96 (m, 4H, (CH ) CH ). LC-MS m/
3
2 2
3
+
z = 400 [M+ H] . Anal. Calcd for C H N OS :S, 57.11;
1
9
23
7
2
H, 4.29; N, 24.54; S, 16.05. Found: S, 57.12; H, 4.30; N,
24.56; S, 16.07.
1
17, 689, 668, 636. H NMR δ (ppm) 9.37 (s, 1H, H-5),
N-(6-methoxy-1,3-benzothiazol-2-yl)-2-([1,2,4]triazolo[1,5-c]
.73 (br. s, 1H, NH), 8.40 (d, J= 7.8Hz, 1H, H-10), 8.03
quinazolin-2-ylthio)acetamide (2b).
Brown solid. Yield:
À1
(d, J = 8.1Hz, 1H, H-7), 7.90 (d, J= 6.8Hz, 1H, H-8),
86.8ꢀ, mp. 200–202°C. IR (cm ) 3215, 3102, 3060,
3019, 2963, 2923, 1703, 1622, 1606, 1574, 1561, 1516,
1484, 1471, 1455, 1431, 1402, 1375, 1362, 1310, 1255,
1227, 1187, 1155, 1113, 1059, 1031, 993, 984, 907, 836,
7
2
.78 (d, J = 7.4 Hz, 1H, H-9), 7.55–7.35 (m, 4H, Ph-
,3,5,6), 4.41 (d, J = 5.5Hz, 1H, HNCH ), 4.07 (s, 2H,
2
+
SCH ). LC-MS m/z =418 [M+ H] . Anal. Calcd for
C H F N OS: S, 54.67; H, 3.38; N, 16.78; S, 7.68.
Found: S, 54.65; H, 3.40; N, 16.81; S, 7.80.
2
1
19 14 3 5
811, 776, 753, 717, 662, 648, 615. H NMR δ (ppm)
12.51 (br. s, 1H, NH), 9.38 (s, 1H, H-5), 8.42 (d,
N-(3-methoxybenzyl)-2-([1,2,4]triazolo[1,5-c]quinazolin-
J = 7.9 Hz, 1H, H-10), 8.01 (d, J = 6.6 Hz, 1H, H-7), 7.87
2
-ylthio)acetamide (1k). Light green solid. Yield: 51.5ꢀ,
(
(
t, J = 7.5 Hz, 1H, H-8), 7.77 (t, J = 7.6 Hz, 1H, H-9), 7.59
d, J = 8.5 Hz, 1H, Ph-8), 7.38 (s, 1H, Ph-5), 6.95 (d,
À1
mp. 154–156°C. IR (cm ) 3275, 3062, 2955, 2921,
2
1
1
8
851, 1646, 1624, 1602, 1540, 1522, 1493, 1473, 1453,
429, 1397, 1372, 1353, 1305, 1265, 1214, 1182, 1167,
103, 1084, 1070, 1040, 1003, 963, 926, 915, 899, 888,
J = 7.3 Hz, 1H, Ph-7), 4.37 (s, 2H, SCH ), 1.24 (s, 3H,
2
+
OCH ). LC-MS m/z = 437 [M + H] . Anal. Calcd for
3
C H N O S : S, 54.02; H, 3.34; N, 19.89; S, 15.18.
20 16 6 2 2
1
41, 795, 776, 747, 718, 692, 641, 623. H NMR δ
Found: S, 59.84; H, 3.41; N, 21.77; S, 15.17.
(ppm) 9.34 (s, 1H, H-5), 8.56 (br. s, 1H, NH), 8.39 (d,
N-(6-chloro-1,3-benzothiazol-2-yl)-2-([1,2,4]triazolo[1,5-c]
J =7.9 Hz, 1H, H-10), 8.02 (d, J =7.7Hz, 1H, H-7), 7.89
quinazolin-2-ylthio)acetamide (2c).
White solid. Yield:
À1
(
(
t, J = 7.6Hz, 1H, H-8), 7.77 (t, J = 7.3Hz, 1H, H-9), 7.10
t, J =7.8 Hz, 1H, Ph-5), 6.79 (d, J =7.6 Hz, 1H, Ph-4),
6
3
1
0.0ꢀ, mp. 271–272°C. IR (cm ) 3201, 3057, 3037,
004, 2959, 2917, 2854, 1697, 1624, 1600, 1553, 1520,
481, 1445, 1400, 1385, 1375, 1357, 1322, 1309, 1258,
6
.76 (s, 1H, Ph-2), 6.67 (d, J= 8.3Hz, 1H, Ph-6), 4.30 (d,
J =5.3 Hz, 2H, NHCH ), 4.04 (s, 2H, SCH ), 3.68 (s, 3H,
2
2
1229, 1162, 1152, 1107, 1096, 1052, 993, 966, 934,
907, 871, 818, 770, 761, 751, 737, 718, 687, 658, 619.
+
OCH ). LC-MS m/z = 380 [M + H] . Anal. Calcd for
3
1
C H N O S: S, 60.14; H, 4.52; N, 18.46; S, 8.45.
19
17
5
2
H NMR δ (ppm) 12.81 (br. s, 1H, NH), 9.37 (s, 1H,
Found: S, 60.12; H, 4.51; N, 18.45; S, 8.47.
N-(4-methoxybenzyl)-2-([1,2,4]triazolo[1,5-c]quinazolin-2-
H-5), 8.39 (d, J = 7.8 Hz, 1H, H-10), 8.02 (d, J = 8.1 Hz,
1
H, H-7), 7.88 (t, J = 7.6 Hz, 1H, H-8), 7.76 (t,
ylthio)acetamide (1l).
Orange solid. Yield: 55.0ꢀ, mp.
J = 7.4 Hz, 1H, H-9), 7.35–7.21 (m, 3H, Ph-5,7,8), 4.36
À1
+
1
1
1
8
9
70–172°C. IR (cm ) 3309, 2950, 2917, 2849, 1666,
621, 1605, 1553, 1511, 1477, 1454, 1396, 1385, 1318,
302, 1241, 1211, 1197, 1171, 1103, 1029, 962, 903,
04, 774, 717, 682, 667, 642, 625. H NMR δ (ppm)
.34 (s, 1H, H-5), 8.57 (br. s, 1H, NH), 8.39 (d,
(
s, 2H, SCH ). LC-MS m/z = 427 [M + H] . Anal. Calcd
2
for C H ClN OS : S, 50.64; H, 2.60; N, 19.69; S,
1
8
11
6
2
1
5.02. Found: S, 50.65; H, 2.61; N, 19.70; S, 15.03.
1
N-(4-Chlorophenyl)-2-([1,2,4]triazolo[1,5-c]quinazolin-2-
ylthio)acetamide (3a).
Brown solid. Yield: 59.0ꢀ, mp.
À1
J =7.9 Hz, 1H, H-10), 8.03 (d, J =7.8 Hz, 1H, H-7), 7.89
t, J= 7.6Hz, 1H, H-8), 7.78 (t, J = 7.3Hz, 1H, H-9),
.13 (d, J = 7.6Hz, 1H, Ph-3,5), 6.72 (d, J= 7.6 Hz, 1H,
H-7, Ph-2,6), 4.25 (d, J =5.3 Hz, 2H, NHCH ), 4.02 (s,
172–174°C. IR (cm ) 3309, 2952, 2921, 2851, 1682,
1622, 1593, 1531, 1516, 1473, 1465, 1454, 1436, 1420,
1396, 1368, 1350, 1314, 1301, 1277, 1262, 1248, 1235,
1189, 1171, 1125, 1102, 1050, 1036, 957, 895, 881, 854,
(
7
2
1
2
+
H, SCH ), 3.67 (s, 3H, OCH ). LC-MS m/z = 380 [M
777, 763, 717, 673, 641. H NMR δ (ppm) 9.64 (br. s,
2
3
+
H] . Anal. Calcd for C H N O S: S, 60.14; H, 4.52;
1H, NH), 9.40 (s, 1H, H-5), 8.44 (d, J = 7.8 Hz, 1H, H-
10), 8.05–8.02 (m, 2H, Ph-5, H-7), 7.90 (t, J =7.3Hz,
1H, H-8), 7.78 (t, J =7.3 Hz, 1H, H-9), 7.36 (d,
J = 7.6 Hz, 1H, Ph-3), 7.26 (t, J = 7.6 Hz, 1H, Ph-4), 7.09
1
9 17 5 2
N, 18.46; S, 8.45. Found: S, 60.12; H, 4.51; N, 18.45;
S, 8.47.
N-(5-butyl-1,3,4-thiadiazol-2-yl)-2-([1,2,4]triazolo[1,5-c]
quinazolin-2-ylthio)acetamide solid. (2a). Brown solid.
Yield: 90.4ꢀ, mp. 176–178°C. IR (cm ) 3391, 3261,
(d, J= 7.5 Hz, 1H, Ph-6), 4.28 (s, 2H, SCH ). LC-MS m/
2
À1
+
z = 370 [M+ H] . Anal. Calcd for C H ClN O: S,
17
12
5
3
1
202, 3056, 2949, 2918, 1624, 1600, 1553, 1520, 1481,
445, 1400, 1384, 1375, 1357, 1332, 1309, 1258, 1229,
55.21; H, 3.27; N, 18.94; S, 8.67. Found: S, 55.20; H,
3.25; N, 18.95; S, 8.65.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
N-(Phenyl, Benzyl, Hetaryl)-2-([1,2,4]Triazolo[1,5-c]Quinazolin-2-ylthio)Acet-
amides Antimicrobial Activity
+
N-(2-bromophenyl)-2-([1,2,4]triazolo[1,5-c]quinazolin-2-
+ H] . Anal. Calcd for C H FN OS: S, 57.78; H, 3.42;
17
12
5
ylthio)acetamide (3b). Brown solid. Yield: 62.0ꢀ, mp.
N, 19.82; S, 9.07. Found: S, 57.75; H, 3.46; N, 19.82; S,
9.08.
À1
1
1
1
1
7
9
86–188°C. IR (cm ) 3307, 2983, 2919, 2850, 1674,
621, 1604, 1588, 1576, 1516, 1475, 1453, 1433, 1392,
374, 1352, 1318, 1300, 1273, 1261, 1240, 1207, 1169,
154, 1106, 1045, 1023, 956, 896, 878, 851, 778, 763,
17, 689, 653. H NMR δ (ppm) 9.53 (br. s, 1H, NH),
.42 (s, 1H, H-5), 8.45 (d, J = 7.8Hz, 1H, H-10), 8.03 (d,
N-(2-(trifluoromethyl)phenyl)-2-([1,2,4]triazolo[1,5-c]
quinazolin-2-ylthio)acetamide (3f).
Light brown solid.
À1
Yield: 45.0ꢀ, mp. 169–171°C. IR (cm ) 3200, 3138,
3065, 3021, 2965, 2940, 2909, 2882, 2830, 1671, 1656,
1624, 1601, 1547, 1537, 1521, 1491, 1480, 1468, 1451,
1426, 1395, 1374, 1353, 1320, 1308, 1284, 1261, 1247,
1220, 1178, 1160, 1153, 1081, 1039, 996, 965, 899, 891,
1
J =8.3 Hz, 1H, H-7), 7.95 (d, J = 8.4Hz, 1H, Ph-3), 7.90
(
(
t, J = 7.7Hz, 1H, H-8), 7.78 (t, J = 7.3Hz, 1H, H-9), 7.53
d, J = 7.9Hz, 1H, Ph-6), 7.31 (d, J = 7.6Hz, 1H, Ph-4),
1
850, 790, 768, 734, 718, 687, 642. H NMR δ (ppm)
7
.03 (t, J = 7.5Hz, 1H, Ph-5), 4.26 (s, 2H, SCH ). LC-
10.20 (br. s, 1H, NH), 9.40 (s, 1H, H-5), 8.43 (d,
J = 8.0 Hz, 1H, H-10), 8.02 (d, J = 8.1 Hz, 1H, H-7), 7.89
(t, J = 7.7 Hz, 1H, H-8), 7.78 (t, J= 7.5 Hz, 1H, H-9),
7.34–7.30 (m, 1H, Ph-6), 7.13 (dd, J = 15.8, 8.0Hz, 2H,
2
+
MS m/z =415 [M +H] . Anal. Calcd for C H BrN OS:
S, 49.29; H, 2.92; N, 16.90; S, 7.74. Found: S, 49.28; H,
1
7
12
5
2
.94; N, 16.92; S, 7.71.
N-(3-bromophenyl)-2-([1,2,4]triazolo[1,5-c]quinazolin-2-
Ph-4,5), 6.55 (d, J = 7.3 Hz, 1H, Ph-3), 4.24 (s, 2H,
+
ylthio)acetamide (3c).
Light green solid. Yield: 60.0ꢀ,
SCH ). LC-MS m/z = 404 [M +H] . Anal. Calcd for
2
À1
mp. 125–127°C. IR (cm ) 3255, 3181, 3122, 3064,
C H F N OS: S, 53.60; H, 3.00; N, 17.36; S, 7.95.
18 12 3 5
2
1
1
7
1
993, 2918, 2850, 1682, 1668, 1621, 1587, 1535, 1516,
478, 1454, 1401, 1385, 1333, 1307, 1283, 1253, 1187,
163, 1146, 1131, 1092, 1071, 1049, 995, 981, 900, 869,
79, 765, 747, 715, 681, 658, 623. H NMR δ (ppm)
0.40 (br. s, 1H, NH), 9.39 (s, 1H, H-5), 8.42 (d,
Found: S, 53.62; H, 3.01; N, 17.34; S, 7.96.
N-(4-(trifluoromethyl)phenyl)-2-([1,2,4]triazolo[1,5-c]
quinazolin-2-ylthio)acetamide (3g).
Yellow solid. Yield:
1
À1
64.0ꢀ, mp. 220–222°C. IR (cm ) 3324, 3063, 1675,
1620, 1602, 1526, 1513, 1483, 1406, 1396, 1377, 1360,
1335, 1302, 1266, 1248, 1185, 1160, 1113, 1068, 1019,
J =7.9 Hz, 1H, H-10), 8.02 (d, J =8.2Hz, 1H, H-7), 7.89
dd, J = 7.1Hz, 2H, H-8, Ph-2), 7.77 (t, J = 7.4Hz, 1H, H-
), 7.21–7.16 (m, 3H, Ph-4-6), 4.24 (s, 2H, SCH ). LC-
1
(
9
971, 904, 866, 835, 783, 771, 715, 656, 612. H NMR δ
(ppm) 10.58 (br. s, 1H, NH), 9.40 (s, 1H, H-5), 8.43 (d,
J = 7.6 Hz, 1H, H-10), 8.02 (d, J = 8.1 Hz, 1H, H-7), 7.89
(t, J = 7.8 Hz, 1H, H-8), 7.79 (dd, J = 15.8, 8.0 Hz, 3H, H-
2
+
MS m/z =415 [M +H] . Anal. Calcd for C H BrN OS:
S, 49.29; H, 2.92; N, 16.90; S, 7.74. Found: S, 49.31; H,
1
7
12
5
2
.93; N, 16.88; S, 7.75.
N-(2-fluorophenyl)-2-([1,2,4]triazolo[1,5-c]quinazolin-2-ylthio)
9, Ph-3,5), 7.55 (d, J = 8.3 Hz, 2H, Ph-2,4), 4.28 (s, 2H,
+
SCH
). LC-MS m/z = 404 [M +H] . Anal. Calcd for
2
acetamide (3d). White solid. Yield: 52.7ꢀ, mp. 114–116°
C. IR (cm ) 3270, 3217, 3135, 3048, 2919, 2850, 1684,
C H F N OS: S, 54.67; H, 3.38; N, 16.78; S, 7.68.
18 12 3 5
Found: S, 54.65; H, 3.40; N, 16.81; S, 7.80.
À1
1
1
1
621, 1603, 1545, 1515, 1488, 1476, 1454, 1395, 1372,
355, 1330, 1301, 1266, 1251, 1233, 1190, 1132, 1101,
034, 962, 899, 841, 807, 768, 742, 717, 697, 684, 643.
N-(4-methylphenyl)-2-([1,2,4]triazolo[1,5-c]quinazolin-2-
ylthio)acetamide (3h). Yellow solid. Yield: 61.0ꢀ, mp.
192–194°C. IR (cm ) 3290, 3056, 2918, 2852, 1662,
À1
1
H NMR δ (ppm) 10.03 (br. s, 1H, NH), 9.39 (s, 1H, H-
1621, 1601, 1539, 1515, 1495, 1475, 1452, 1393, 1374,
1356, 1322, 1303, 1263, 1247, 1216, 1182, 1167, 1103,
1075, 1040, 1018, 1003, 985, 964, 937, 902, 877, 839,
5
), 8.44 (d, J = 7.7 Hz, 1H, H-10), 8.02 (t, J = 7.0 Hz, 1H,
H-7), 7.90 (t, J = 7.8Hz, 1H, H-8), 7.79 (t, J= 7.7 Hz,
1
1
H, H-9), 7.13–7.08 (m, 4H, Ph-3-6), 4.28 (s, 2H,
814, 792, 772, 747, 717, 691, 641. H NMR δ (ppm)
+
SCH ). LC-MS m/z =354 [M+ H] . Anal. Calcd for
C H FN OS: S, 57.78; H, 3.42; N, 19.82; S, 9.07.
Found: S, 57.79; H, 3.45; N, 19.80; S, 9.09.
10.11 (br. s, 1H, NH), 9.39 (s, 1H, H-5), 8.42 (d,
J = 7.8 Hz, 1H, H-10), 8.02 (d, J = 8.0 Hz, 1H, H-7), 7.89
(t, J= 6.9 Hz, 1H, H-8), 7.78 (t, J = 7.3 Hz, 1H, H-9), 7.46
(d, J= 7.7 Hz, 2H, Ph-2,6), 7.04 (d, J= 8.0 Hz, 1H, Ph-
2
17
12
5
N-(4-fluorophenyl)-2-([1,2,4]triazolo[1,5-c]quinazolin-2-ylthio)
acetamide (3e).
Light brown solid. Yield: 56.8ꢀ, mp.
3,5), 4.23 (s, 2H, SCH
2
), 2.29 (s, 3H, CH ). LC-MS m/
z = 350 [M+ H] . Anal. Calcd for C18H N OS: S, 61.87;
15 5
3
À1
+
2
2
1
1
9
37–239°C. IR (cm ) 3130, 3084, 2919, 2851, 2772,
652, 2577, 1658, 1650, 1632, 1620, 1563, 1556, 1537,
530, 1504, 1461, 1411, 1384, 1329, 1289, 1266, 1225,
210, 1156, 1137, 1124, 1090, 1061, 1024, 978, 958,
H, 4.33; N, 4.58; S, 9.18. Found: S, 61.88; H, 4.35; N.
4.60; S, 9.20.
N-(4-methoxyphenyl)-2-([1,2,4]triazolo[1,5-c]quinazolin-2-
ylthio)acetamide (3i). Light green solid. Yield: 68.1ꢀ, mp.
1
02, 868, 856, 829, 803, 771, 737, 704, 675, 641. H
-
1
NMR δ (ppm) 10.52 (br. s, 1H, NH), 9.37 (s, 1H, H-5),
214–216°C. IR (cm ) 3298, 3045, 2977, 2927, 2840,
1660, 1616, 1601, 1541, 1510, 1475, 1451, 1412, 1389,
1373, 1356, 1330, 1301, 1247, 1235, 1179, 1166, 1104,
1033, 983, 960, 935, 902, 878, 831, 795, 769, 717, 694,
8
7
.43 (d, J = 7.8Hz, 1H, H-10), 8.03 (d, J = 8.1Hz, 1H, H-
), 7.89 (t, J= 7.5Hz, 1H, H-8), 7.77 (t, J= 7.5Hz, 1H,
H-9), 7.21 (d, J = 8.0Hz, 2H, Ph-3,5), 7.20 (d, J= 8.1 Hz,
H, Ph-2,6), 4.15 (s, 2H, SCH ). LC-MS m/z = 354 [M
1
2
654, 641. H NMR δ (ppm) 10.06 (br. s, 1H, NH), 9.39
2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

L. M. Antypenko, S. I. Kovalenko, T. S. Los' and O. L. Rebec'
Vol 000
(
s, 1H, H-5), 8.42 (d, J = 7.7Hz, 1H, H-10), 8.01 (d,
to identify highly correlated descriptors in order to detect
redundancy in the data set. Hence, descriptors with con-
stant variables and near-constant variables were excluded
from the further consideration (r≥ 0.95) [11,12].
J =7.9 Hz, 1H, H-7), 7.88 (t, J =7.4 Hz, 1H, H-8), 7.77 (t,
J =7.4 Hz, 1H, H-9), 7.50 (d, J =8.5 Hz, 2H, Ph-2,6),
6
.79 (d, J = 8.4Hz, 2H, Ph-3,5), 4.21 (s, 2H, SCH ), 3.74
2
+
(s, 3H, OCH ). LC-MS m/z = 366 [M + H] . Anal. Calcd
The genetic algorithm (GA) and multiple linear regres-
sion analysis (MLRA) were used to select the descriptors
and to generate the correlation models that relate the struc-
tural features to the cell growth percent of different cancer
cell lines. The combination of the GA–MLRA technique
was applied to obtain the best QSAR models using the
QSARINS 2.2. The latter program splitted compounds data
as following: random selection of 20ꢀ of compounds for
prediction set and 80ꢀ for training set. For each obtained
model, such random selection was different [13,14].
Calculation of QSAR-models was conducted separately for
each of 60 cell lines. Growth percent according to the NCI
protocol was not converted to any other value; it was used
in original version to built models. Some cell lines were given
the value of À999, which means, that they were not tested.
The amount of generation algorithm setup was set until
four descriptors, and generation per size was established
to the value of 3000, and the division into training and test
sets was performed automatically at a ratio of 80 to 20ꢀ
relatively. Models, which showed statistical significance
3
for C H N O S: S, 58.28; H, 3.45; N, 19.99; S, 9.15.
Found: S, 58.30; H, 3.47; N. 20.01; S, 9.16.
17 12 5 2
2
-{[([1,2,4]triazolo[1,5-c]quinazolin-2-ylthio)acetyl]amino}
benzoic acid (3j). White solid. Yield: 64.5ꢀ, mp. 234–
À1
2
1
1
7
1
36°C. IR (cm ) 2917, 2851, 1842, 1695, 1668, 1589,
520, 1474, 1450, 1409, 1385, 1353, 1308, 1265, 1248,
217, 1163, 1107, 1093, 1050, 959, 930, 910, 803, 762,
1
37, 715, 696, 661, 651. H NMR δ (ppm) 13.32 (br. s,
H, OH), 11.95 (br. s, 1H, NH), 9.39 (s, 1H, H-5), 8.43
(d, J= 7.8Hz, 1H, H-10), 8.18 (d, J = 6.1Hz, 1H, Ph-3),
8
8
.01 (d, J = 8.0Hz, 1H, H-7), 7.87 (d, J= 6.1Hz, 2H, H-
), 7.77 (t, J= 7.5Hz, 1H, H-9), 7.63 (t, J= 7.3Hz, 1H,
Ph-4), 7.34 (t, J= 7.8Hz, 1H, Ph-5), 7.35 (d, J= 7.8 Hz,
H, Ph-6), 4.21 (s, 2H, SCH ). LC-MS m/z = 380 [M
1
+
2
+
H] . Anal. Calcd for C H N O S: S, 56.98; H, 3.45;
19 15 5 2
N,18.46; S, 8.45. Found: S, 56.99; H, 3.45; N. 18.41; S,
.45.
8
3
-{[([1,2,4]triazolo[1,5-c]quinazolin-2-ylthio)acetyl]amino}
benzoic acid (3k). White solid. Yield: 69.0ꢀ, mp. 242–
À1
2
1
1
9
6
44°C. IR (cm ) 3011, 2898, 1705, 1680, 1646, 1613,
567, 1556, 1512, 1488, 1477, 1454, 1437, 1393, 1373,
334, 1304, 1254, 1240, 1225, 1146, 1104, 1082, 987,
56, 917, 900, 892, 867, 807, 785, 766, 749, 712, 676,
2
according to the parameters at a higher level (r ≥ 0.5),
were selected for a more thorough rendering. For these
lines, the following options were given: the amount of gen-
eration algorithm setup was set until seven descriptors, and
generation per size was established to the value of 10,000.
Substances were spited into training and test sets, and the
division was made such as to establish equal distribution
of substances of high and moderate percentage of inhibi-
tion of cell growth.
1
53. H NMR δ (ppm) 12.61 (br. s, 1H, OH), 10.42
(br. s, 1H, NH), 9.38 (s, 1H, H-5), 8.42 (d, J =7.7 Hz,
1
7
H, H-10), 8.18 (s, 1H, Ph-2), 8.01 (d, J = 8.0Hz, 1H, H-
), 7.87 (d, J= 6.2Hz, 2H, H-8, Ph-6), 7.77 (t,
J =7.5 Hz, 1H, H-9), 7.63 (d, J = 7.3Hz, 1H, Ph-4), 7.35
t, J = 7.7Hz, 1H, Ph-5), 4.25 (s, 2H, SCH ). LC-MS m/
(
2
Docking, scoring, and visual inspection of synthesized
+
z =380 [M+ H] . Anal. Calcd for C H N O S: S,
1
8
13
5
3
substances into the enzymes binding sites.
Flexible
5
3
6.98; H, 3.45; N,18.46; S, 8.45. Found: S, 57.01; H,
.46; N. 18.48; S, 8.47.
molecular docking was carried out using the software
package OPENEYE by the reported earlier procedure [3,15–17].
Quantitative structure–activity relationship-modeling.
Antimicrobial and antifungal activity.
Agar-diffusion
Firstly, all structures were built by MarvinSketch 6.3.0
10]. Then, they were preliminary optimized by program
method was used for determination of the preliminary
in vitro antibacterial and antifungal activity in
Zaporizhzhya Regional Hospital Bacterial Laboratory
against Gram positive bacteria (S. aureus ATCC 25923,
[
HyperChem 8.0.8 using molecular mechanical MM+
algorithm combined with semi-empirical PM3 molecular
modeling method with a maximum number of cycles and
Polak-Ribiere (Conjugate Gradient) algorithm. Molecular
mechanics have been used to produce more realistic
geometry values for the majority of organic molecules
owing to the fact of being highly parameterized. The next
step was a re-optimization of the MM+ optimized
structures by applying semi-empirical PM3 molecular
modeling method. Obtained files were further used for
calculations.
Enterococcus
faecalis
ATCC
29212,
hospital
Streptococcus spp.) and Gram negative bacteria
(Enterobacter aerogenes 12, Cronobacter sakazakii
ATCC BAA-894, P. aeruginosa ATCC 27853, E. coli
ATCC 25922, Klebsiella pneumonia 68) according to the
earlier reported procedure [3].
RESULTS AND DISCUSSION
Descriptors were calculated using Dragon 5.5 (>1500
descriptors) [11]. The correlation coefficients for all pair
of descriptor variables used in the models were evaluated
Chemistry. The following amides (1.1–1.5; 2.1–2.13;
3.1–3.8) were synthesized by classical methods, namely
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
N-(Phenyl, Benzyl, Hetaryl)-2-([1,2,4]Triazolo[1,5-c]Quinazolin-2-ylthio)Acet-
amides Antimicrobial Activity
alkylation of the potassium salt 1 by halogen-acylamides
A–C) refluxing in propan-2-ol-water solution (3:1).
H-7 to the 8.02–8.01ppm, triplets H-8 to the 7.88–
7.87 ppm, and H-9 to the 7.77–7.76ppm. The signals of ar-
omatic 3a–3k amides were the following: singlet H-5
(9.42–9.37ppm), doublets H-10 (8.45–8.42ppm) and H-7
(8.03–8.01ppm), triplets H-8 (7.90–7.87ppm), and H-9
(7.79–7.77ppm). One proton broadened singlet of NH
group of benzyl amides 1a–1l was fixed in the aromatic
part of the spectrum at the 8.73–8.56 ppm, for heterocyclic
amides 2a–2c appeared at the 12.81–12.51 ppm and at the
11.95–9.53ppm – for phenyl amides 3a–k. Considering
(
Reaction went smoothly with formation of the following
amides (Fig. 2).
1
Spectral data (FT-IR, LC-MS, H NMR) and elemental
analysis confirmed the structure of synthesized substances
and corresponded to the previous [1,2,4]triazolo[1,5-c]
quinazoline derivatives data [2–5].
In LC-MS spectra, all compounds had a high-intensive
+.
peaks of [M+H] in accordance with their molecular weight.
In IR spectra, the synthesized amides had vibrations of
two proton singlet of SCH -group, it resonated at the
2
À1
the carbonyl band at the 1680–1635 cm for the second-
4.09–4.02ppm for 1a–1l, 4.37–4.34 ppm for 2a–2c, and
at the 4.28–4.15ppm for 3a–3k. For substances 3i and 3j,
the spectra were characterized by broadened one protoned
singlet of COOH group at the 13.32 and the 12.61 ppm.
The phenyl protons of amides were found in the aromatic
part of the spectrum, alkyl – in the strong field with appro-
priate multiplicity.
À1
ary amides 1a–1l, which shifted to the 1680–1630 cm
for aryl substituted amides 3a–3k. Stretching NH was de-
À1
tected as multiplet at the 3307–3324cm . Intensive bands
À1
of νC-N and δN-H appeared at the 1556–1517cm – for al-
À1
iphatic amides and at the 1556–1516 cm – for aryl am-
ides. The intense vibrations of CCl bond of substances
À1
1
a–1c, 3a were registered in the 746–717cm region,
Antimicrobial activity
À1
CBr for 1d, 1e, 3b, 3c at the 658–623cm , CF for 1f–
h and 3d, 3e at the 1101–1005cm . Vibrations of CF3-
In vitro studies.
All synthesized substances were
À1
1
investigated in vitro by agar-diffusion method in
concentration of 5mg/disk against Gram positive bacteria
S. aureus and E. faecalis; Gram negative bacteria E.
aerogenes, P. aeruginosa, C. sakazakii, E. coli and K.
pneumonia; antifungal properties against C. albicans,
using inhibition zone diameter (mm) as a measure for the
antimicrobial activity (Table 1).
Ar were presented as the middle and strong intensive peaks
À1
À1
at the 1323–1310cm and the 1185–1178 cm
In
.
1
H-NMR spectra, the [1,2,4]triazolo[1,5-c]
quinazoline system of substances 1a–1l was characterized
by the following signals: singlet of H-5 at the 9.37–
9
.34ppm, doublets H-10 at the 8.47–8.37ppm and H-7 at
the 8.03–8.02ppm, triplets H-8 at the 7.90–7.88ppm and
H-9 at the 7.78–7.77 ppm correspondingly to the previous
data [5,9]. The signals of heterocyclic 2a–2c amides
shifted a little bit to the low field: singlet H-5 to the
Unfortunately, E. aerogenes, P. aeruginosa, C. sakazakii,
K. pneumonia, and C. albicans were insensitive to all syn-
thesized compounds, and substances 1b–1d, 1f, 1h–1k, 2c,
3a–3d, and 3f–3i had no activity against all investigated mi-
crobial strains.
9
.38–9.36 ppm, doublets H-10 to the 8.42–8.39 ppm, and
Figure 2. Synthesis of 2-([1,2,4]triazolo[1,5-c]quinazolin-2-ylsulfanyl)acetamides.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

L. M. Antypenko, S. I. Kovalenko, T. S. Los' and O. L. Rebec'
Vol 000
Table 1
antimicrobial activity manifestation against S. aureus and
E. faecalis.
The inhibitory zones of the synthesized compounds, mm.
In silico studies
Conc.
a
Molecular docking to E. faecalis dihydrofolate reductase.
To predict the possible antibacterial mechanism of
substances as well as to compare in silico results with
in vitro, it was decided to conduct flexible molecular
docking of the synthesized compounds [16].
Dihydrofolate reductase (DHFR) is a classic drug target,
because it promotes the NADPH-dependent reduction of
Compd.
mg/disk
E. coli
S. aureus
E. faecalis
b
c
1
1
1
1
2
2
3
3
3
a
e
g
l
a
b
e
j
5
5
5
5
5
5
5
5
6
6
10
8
6
9
7
6
6
6
6
6
6
6
15
0
16
0
6
6
8
6
7
13
6
6
0
0
6
15
10
6
21
18
11
7
,8-dihydrofolate to yield 5,6,7,8-tetrahydrofolate, which
is involved in the biosynthesis of purines, thymidylate,
and several amino acids in microbial cells [18]. Moreover,
investigation of hydrophobic heterocyclic dihydrophthalazines
series, which were designed from antifolate drug trimetho-
prim, the propyl and trifluoropropyl substituents had an im-
portant role in protein stability during catalytic cycling, due
to flexibility – an important determinant to fit into the inhib-
itor, thereby allowing it to take advantage of any available
subpockets of the binding site [19].
k
5
Oxacillin
Vancomycin
Nystatin
0.1
0.1
0.1
15
a
Substances 1b–1d, 1f, 1h–1k, 2c, 3a–3d, 3f–3i had no activity.
Disk diameter.
Bold values mean active compounds.
E. coli, Escherichia coli; S. aureus, Staphylococcus aureus; E. faecalis,
Enterococcus faecalis.
b
c
Only nine substances had from light to moderate anti-
bacterial activities. The best one was shown by N-(4-
fluorophenyl)-2-([1,2,4]triazolo[1,5-c]quinazolin-2-ylthio)
acetamide 3e, which inhibited growth of S. aureus at the
The software package «OPENEYE» was used for studies,
including utilities: Fred Receptor 2.2.5, Vida 4.1.1, Flip-
per, Babel 3, Omega 2.4.3 and Fred 2.2.5 [15].
The crystal structure of the enzyme E. faecalis DHFR
(4M7U.pdb) was obtained from the protein data bank,
and Trimetoprim was used as reference [17,19].
The obtained scoring functions (Shapegauss, PLP,
Chemgauss2, Chemgauss3, Chemscore, OEChemscore,
Screenscore, CGO, CGT, Zapbind, Consensus Score) indi-
cated the best possibility of the matching into the ligand-
protein complex (Table S2).
Practically, all substances had better consensus scores,
than Trimetoprim, except of 3g. All heterocyclic amides,
namely, substance 2b had practically five times better af-
finity, than the reference, and 2a with 2c had a little bit
worth result, still high enough.
1
5mm and E. faecalis at the 13 mm. Interestingly, that
compound 3d with practically the same structure had no
effect.
Besides, E. coli was sensitive only to 3-{[([1,2,4]triazolo
[1,5-c]quinazolin-2-ylthio)acetyl]amino}benzoic acid 3k,
despite practically the same structure of 3j. The light effect
on the S. aureus growth was made by 1e, 1g, 2a, and 3j,
and against E. faecalis by 1a and 1l, but still in lower, than
the references concentration.
Comparing the obtained antimicrobial results with previ-
ous reported ones, it was found that introduction of hetaryl,
4-fluorophenyl and benzoic acid residues lead to the
Figure 3. Visual representation of a receptor–ligand interaction: active site of Enterococcus faecalis dihydrofolate reductase (4M7U.pdb) with
Trimetoprim (A) and N-(6-methoxy-1,3-benzothiazol-2-yl)-2-([1,2,4]triazolo[1,5-c]quinazolin-2-ylthio)acetamide 2b (B), which has the highest Consen-
sus Score. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
N-(Phenyl, Benzyl, Hetaryl)-2-([1,2,4]Triazolo[1,5-c]Quinazolin-2-ylthio)Acet-
amides Antimicrobial Activity
The visual inspection demonstrated that substituents at
the second position were flexible enough to be rotated by
the Sulfur bond and intercorporated in the same enzyme
pocket as Trimetoprim (Fig. 3), although no hydrogen
bonds were formed.
The good impact for the affinity was made by 3-OCH3,
2
-CF 2-F, 2-Cl radicals in phenyl residue in series 1 and
3,
3. Interestingly, that the weakest substance 3g, that differed
from 1j just by the absence of CH fragment had the worst
2
Consensus Score in 116 points.
Molecular docking to UDP-N-acetylglucosamine enolpyruvyl
transferase. The essential enzyme UDP-N-acetylglucosamine
enolpyruvyl transferase (MurA) that was involved in the
biosynthesis of peptidoglycan of cell wall was also chosen to
be investigated for molecular docking. Because Mur enzymes
are absent in humans and have no human homologues, its
inhibition represents a promising point of study [20,21].
Thus, MyrAec from E. cloacae (1Q3G.pdb) was used
for investigation [20]. The T6361 (2-(N-methyl-5-
Figure 5. Correlation graph of predicted versus experimental growth
percentage for model equation against Streptococcus sp. [Color
figure can be viewed in the online issue, which is available at
wileyonlinelibrary.com.]
(naphthalen-1-ylsulfonyloxy)-2-(naphthalene-1-sulfon-amido)
benzamido)-succinic acid, which was proven to inhibit MurA
and MurZ of E.faecalis, was used as the reference [21].
No substances suppressed the T6361 by affinity into the
Hitherto, analyzing substances’ structure with the best
consensus scores (3k, 1k, and 1b), among the most impor-
tant factors to fit into enzyme were the following: the third
MyrA binding site (Table S3). Visual inspection also had
shown the sterical restrictions of the structures to fit into its
pocket (Fig. 4).
ec
Figure 4. Visual representation of a receptor–ligand interaction: active site of Enterobacter cloacae MyrAec (1Q3G.pdb) with T6361 (A) and 3-{[([1,2,4]
triazolo[1,5-c]quinazolin-2-ylthio)acetyl]amino}-benzoic acid 3k (B), which has the highest consensus score. [Color figure can be viewed in the online
issue, which is available at wileyonlinelibrary.com.]
Table 2
The best QSAR-model’s statistical characteristics.
Training set*
Prediction set
2
2
2
n
9
r
RMSE
0.9145
s
F
Q
LOO
n
14
r
RMSE
1.7155
5
0.6489
0.9472
33.8846
0.4856
0.4956
2
*
n, number of investigated compounds in set, r , squared regression coefficient, RMSE, root mean square error, s, standard error, F, variance ratio, Fisher
2
coefficient, Q LOO, weighted correlation coefficient by leave-one out method.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

L. M. Antypenko, S. I. Kovalenko, T. S. Los' and O. L. Rebec'
Vol 000
position of the substituent in the phenyl ring, the possibility
QSAR studies based on the already reported
antimicrobial data of the 2-thiosubstituted [1,2,4]
triazolo[1,5-c]quinazolines with consequent prediction
of the antimicrobial potential for all their synthesized
2-thio series (Table S4, Mol files) [2–5].
of the phenyl ring rotation, due to NHCH fragment presence
2
for compounds 1d and 1i, and absence of the F, Br, CH and
3
CF radicals in phenyl ring.
3
Hence, according to the docking results, inhibition of
the MyrA was doubtable to be the possible way of activ-
The program QSARINS 2.2 calculated the best regression
using descriptors obtained by Dragon 5.5 [13,14]. Because
of their very high quantity, GA and MLRA were used.
Hence, all bacteria and fungi strains were analyzed, and
substances descriptors were found, but only one equation
against Streptococcus sp. had squared regression coeffi-
e
ity, although the most active substance 3k effected the
growth of E. coli, but inhibition of DHFR could be sug-
gested as one of the possible antimicrobial activity mech-
anism, although according to in vitro results series 2 had
poor antimicrobial activity.
Yet, the presence of the proposed mechanisms should be
proven by subsequent enzymatic studies, which we still
had no opportunity to do.
2
cient (r ) at least 0.6489, and weighted correlation coeffi-
2
cient by leave-one out method (Q LOO) was 0.4856, due
to analyzed variance with low exhibited in vitro antibacte-
rial activity (Table 2, Fig. 5).
Upon these data, the simple transparent and realistic
QSAR model was proposed to avoid errors arising from
Quantitative structure–activity relationship studies.
Considering the low antimicrobial properties of the
synthesized compounds, it was decided to conduct
Table 3
Experimental data of substances in vitro antimicrobial activity in comparison to predicted by QSAR-model, mm.
a
Cmpd.
Status
In vitro
Predicted
Cmpd
Status
In vitro
Predicted
LA-45
Prediction
Training
Training
Training
Prediction
Training
Training
Training
Training
Training
Prediction
Training
Training
Training
Prediction
Training
Training
Training
Training
Training
Training
Prediction
Training
Training
Training
Training
Training
Training
Training
Training
Training
Training
Training
Training
Prediction
Training
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
5.36
5.47
5.49
5.51
5.59
5.61
5.63
5.66
5.68
5.74
5.74
5.80
5.82
5.82
5.82
5.82
5.84
5.84
5.84
5.86
5.90
5.90
5.90
5.93
5.95
5.95
5.95
5.95
5.97
6.05
6.05
5.99
5.99
6.01
6.01
7.93
MN-44
MN-56
MN-52
LA-16
LA-13
MN-54
MN-66
MN-53
LA-23
LA-185
LA-256
LA-40
LA-259
LA-5
Prediction
Training
Training
Training
Training
Training
Training
Training
Training
Training
Training
Prediction
Training
Training
Training
Training
Training
Training
Prediction
Training
Training
Prediction
Prediction
Training
Training
Prediction
Prediction
Prediction
Training
Training
Training
Training
Training
Training
Training
-
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
8
6
11
6
6
6
12
6
6
6
6
6
13
11
11
13
-
6.07
6.11
6.13
6.14
6.16
6.16
6.18
6.20
6.22
6.24
6.28
6.43
6.47
6.51
6.59
6.61
6.68
6.84
6.85
7.26
7.32
7.36
7.40
7.42
7.45
7.65
7.65
7.65
7.88
5.97
5.97
8.07
8.66
11.84
12.16
-
MN-17
LA-26
LA-28
LA-12
MN-13
LA-3
LA-29
MN-69
MN-50
MN-67
MN-12
LA-47
MN-46
MN-64
MN-68
LA-102
LA-44
LA-84
LA-46
LA-14
MN-58
MN-62
MN-60
LA-183
MN-55
MN-57
MN-59
MN-45
MN-49
MN-61
LA-10
MN-51
LA-80
MN-65
LA-48
LA-2
LA-27
LA-15
LA-1
LA-254
LA-177
LA-178
LA-232
LA-230
LA-216
LA-211
LA-139
LA-200
LA-49
LA-187
MN-47
MN-48
LA-186
LA-39
LA-50
LA-255
-
a
Original names of compounds were used not to be confused with each other, because of the same numbering in different articles (Supporting Information,
mol files).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
N-(Phenyl, Benzyl, Hetaryl)-2-([1,2,4]Triazolo[1,5-c]Quinazolin-2-ylthio)Acet-
amides Antimicrobial Activity
Figure 6. The most active compounds predicted in silico by QSAR model among 2-thiosubstituted [1,2,4]triazolo[1,5-c]quinazolines and their 2-(2-R-
H-1,2,4-triazol-5-yl)aniline analogues against Streptococcus species.
1
over-fitting of data: 19.1944*R3e++1.963*O-056
4.4204*O-059+4.5322. So, the essential descriptors
were R3e: weighted by atomic Sanderson electronegativ-
ities – R autocorrelation of lag 3, atom centered fragments:
O-056 – alcohol and O-059 – Alk-O-Alk [12].
The prediction of the antimicrobial activity by the calculated
QSAR model showed its moderate accuracy (Table 3).
Then, the calculated QSAR model was used to predict
antimicrobial properties against Streptococcus sp. by other
amino}benzoic acid 3k were the strongest ones. The flexibility
of thio substituents as well as the presence of the benzoic acid,
hetaryl and 4-fluorophenyl fragments appeared to be the
crucial factors for substances to be antimicrobials.
+
Thus, the reported results indicated that in vitro screen-
ing was a significant and important methodology as the
starting point of drug candidates’ search, even with good
in silico molecular docking results [22]. Moreover, the best
way of future modifications to manifest [1,2,4]triazolo[1,5-
c]quinazolines’ antibacterial activity will be hetaryl groups
introduction directly into the 2nd position according to the
QSAR prediction, and considering already reported posi-
tive results among potassium 2-hetaryl-[1,2,4]triazolo
[1,5-c]quinazoline-5-thiolates, removing the thio group
from the 2nd into the 5th position.
2
70 reported and unreported 2-thio-substituted [1,2,4]
triazolo[1,5-c]quinazolines (Table S5).
Only 12 substances had at least 10–12 mm of growth
inhibition predicted. The best results were predicted for
alcohols, 2,4-dinitrophenyl derivative and morpholino
substituted
amides of 2-thio-[1,2,4]triazolo[1,5-c]
quinazoline carboxylic acids (Fig. 6, Table S6).
Moreover, nucleophilic degradation to 2-(1H-1,2,4-
triazol-5-yl)anilines and direct introduction into [1,2,4]
triazolo[1,5-c]quinazoline second position of the morpholine
heterocycle also had positive impact for exhibiting the anti-
microbial activity.
Acknowledgments. The authors gratefully acknowledge “Enamine
Ltd.” (Kiev, Ukraine) for financial support of this work.
REFERENCES AND NOTES
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without chemical modifications in the fifth position or ben-
zene ring of quinazoline mojety.
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L. M. Antypenko, S. I. Kovalenko, T. S. Los' and O. L. Rebec'
Vol 000
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