Antimicrobial activities of some synthesized 1-(3-(2-methylphenyl)-4-Oxo-3H-quinazolin-2-yl-4-(substituted)thiosemicarbazide derivatives

Article abstract of DOI:10.1134/S106816201603002X

The substituted thiosemicarbazide moiety was placed at the C-2 position and 2-methylphenyl group at N-3 position of quinazoline ring and obtained compounds were tested for their antitubercular activities and antibacterial activities against selected gram-positive and gram-negative bacteria. The target compounds 1-(3-(2-methylphenyl)-4-oxo-3H-quinazolin-2-yl)-4-(substituted) thiosemicarbazides were obtained by the reaction of 2-hydrazino-3-(2-methylphenyl) quinazolin-4(3H)-one with different dithiocarbamic acid methyl ester derivatives. All synthesized compounds were also screened for their antimicrobial activity against selective gram-positive and gram-negative bacteria by agar dilution method. Among the series, 1-[3-(2-methylphenyl)-4-oxo-3H-quinazolin-2-yl]-4-[4-chlorophenyl]-thiosemicarbazide exhibited the most potent activity against S. typhi, E. coli, and B. subtilis, while 1-[3-(2-methylphenyl)-4-oxo-3H-quinazolin-2-yl]-4-[4-nitrophenyl]-thiosemicarbazide was the most potent against E. coli, B. subtilis, P. aeruginosa, S. typhi, and S. flexneri. These two compounds exhibited the antitubercular activity at the minimum concentration (3 μg/mL) that offered potential for further optimization and development of new antitubercular agents. The obtained results demonstrated promising antimicrobial and antitubercular activities of the synthesized quinazoline compounds which could be used as new scaffolds for improving their antimicrobial activity.

Full text of DOI:10.1134/S106816201603002X

ISSN 1068ꢀ1620, Russian Journal of Bioorganic Chemistry, 2016, Vol. 42, No. 3, pp. 332–339. © Pleiades Publishing, Ltd., 2016.
Antimicrobial Activities of Some Synthesized
1ꢀ(3ꢀ(2ꢀMethylphenyl)ꢀ4ꢀOxoꢀ3HꢀQuinazolinꢀ2ꢀylꢀ4ꢀ
(Substituted)Thiosemicarbazide Derivatives1
2
V. Alagarsamya, , G. V. Anjanab, M. T. Sulthanaa, P. Parthibana, and V. Raja Solomona, c
a Medicinal Chemistry Research Laboratory, MNR College of Pharmacy, Sangareddy, Gr. Hyderabad, 502294 India
b Department of Pharmaceutical Chemistry, Dale View College of Pharmacy and Research Centre,
Punalal P.O., Thiruvananthapuram, 695575 India
c Faculty of Pharmacy, the University of Sydney, Sydney, NSW 2006 Australia
Received June 3, 2015; in final form, November 13, 2015
Abstract—The substituted thiosemicarbazide moiety was placed at the Cꢀ2 position and 2ꢀmethylphenyl
group at Nꢀ3 position of quinazoline ring and obtained compounds were tested for their antitubercular activꢀ
ities and antibacterial activities against selected gramꢀpositive and gramꢀnegative bacteria. The target comꢀ
pounds 1ꢀ(3ꢀ(2ꢀmethylphenyl)ꢀ4ꢀoxoꢀ3Hꢀquinazolinꢀ2ꢀyl)ꢀ4ꢀ(substituted) thiosemicarbazides were
obtained by the reaction of 2ꢀhydrazinoꢀ3ꢀ(2ꢀmethylphenyl) quinazolinꢀ4(3
bamic acid methyl ester derivatives. All synthesized compounds were also screened for their antimicrobial
activity against selective gramꢀpositive and gramꢀnegative bacteria by agar dilution method. Among the
series, 1ꢀ[3ꢀ(2ꢀmethylphenyl)ꢀ4ꢀoxoꢀ3 ꢀquinazolinꢀ2ꢀyl]ꢀ4ꢀ[4ꢀchlorophenyl]ꢀthiosemicarbazide exhibꢀ
ited the most potent activity against S. typhi, E. coli, and B. subtilis, while 1ꢀ[3ꢀ(2ꢀmethylphenyl)ꢀ4ꢀoxoꢀ3
H)ꢀone with different dithiocarꢀ
H
H
ꢀ
quinazolinꢀ2ꢀyl]ꢀ4ꢀ[4ꢀnitrophenyl]ꢀthiosemicarbazide was the most potent against E. coli, B. subtilis,
P. aeruginosa, S. typhi, and S. flexneri. These two compounds exhibited the antitubercular activity at the minꢀ
imum concentration (3 g/mL) that offered potential for further optimization and development of new antiꢀ
µ
tubercular agents. The obtained results demonstrated promising antimicrobial and antitubercular activities of
the synthesized quinazoline compounds which could be used as new scaffolds for improving their antimicroꢀ
bial activity.
Keywords: quinazolinone, substituted thiosemicarbazide, antiꢀbacterial activity, antitubercular activity
DOI: 10.1134/S106816201603002X
INTRODUCTION
ure) showed significant antitubercular activity [5]. The
thiosemicarbazide and thiosemicarbazone pharmaꢀ
cophore groups in different heterocyclic moieties
(compounds (III) and (IV) in the figure) were also
found to exhibit the antitubercular activity [6–14].
The present work is an extension of our ongoing efforts
towards developing effective antitubercular and antiꢀ
microbial agents by a hybrid approach using the
quinazoline scaffold (figure). In this approach, two or
more pharmacophores are merged into a single molꢀ
ecule. Therefore, each of the pharmacophores in a
single molecule may be addressing the active site of
targets and offers the selectivity; furthermore, this
may also reduce unwanted side effects [15]. In the
present study, we placed the substituted thiosemicarꢀ
bazide moiety at the Cꢀ2 position and 2ꢀmethylpheꢀ
nyl group at the Nꢀ3 position of quinazoline ring [16,
17] and studied their antitubercular and antibacterial
activities against selected gramꢀpositive and gramꢀ
negative bacteria.
Tuberculosis (TB) is one of the leading causes of
death all over the world. This infection is caused priꢀ
marily in the lungs (a pneumonia) by bacteria Mycoꢀ
bacterium tuberculosis. Emergence of multi drug resisꢀ
tant tuberculosis (MDRꢀTB) makes the situation the
most alarming [1, 2]. Some of the MDR isolates are
resistant to as many as seven of the commonly
employed antiꢀmycobacterial drugs [3]. Quinazolines
and condensed quinazolines received the attention of
medicinal chemists due to their potential biological
activities. Among the biological activities exhibited by
quinazolines, the antimicrobial activities of 2,3ꢀdisubꢀ
stituted quinazolines are promising [4]. Literature surꢀ
vey indicated that the quinazoline nucleus substituted
at positions 2 and 3 (compounds (I) and (II) in the figꢀ
1
The article is published in the original.
Corresponding author: phone: +91 8455ꢀ230690; fax: +91
8455ꢀ230 555; eꢀmail: drvalagarsamy@gmail.com.
2
332

ANTIMICROBIAL ACTIVITIES OF SOME SYNTHESIZED THIOSEMICARBAZIDES
S
333
O
O
N
R
R
N
R1
H3C
O
H3C
N
H
N
S
H
N
N
N
H
H
R2
N
N
S
N
R
N
R
(
III)
S
O
(
I
)
(II)
R1
N
O
N
N
H
H
Hybrid approach
R1
N
R
(
IV
)
H3C
O
N
H
H
N
N
R
N
N
H
S
(
XIIa–j)
Hybrid approach to design of 1ꢀ[3ꢀ(2ꢀmethylphenyl)ꢀ4ꢀoxoꢀ3Hꢀquinazolinꢀ2ꢀyl]ꢀ4ꢀ[substituted]ꢀthiosemicarbazide analogues.
RESULTS AND DISCUSSION
reflux with methyl anthranilate (VII) in ethanol yieldꢀ
ed the desired 3ꢀ(2ꢀmethylphenyl)ꢀ2ꢀthioxoꢀ2,3ꢀdihyꢀ
droꢀ1 ꢀquinazolinꢀ4ꢀone (VIII) via the thiourea interꢀ
mediate in good yield (86%). The 3ꢀ(2ꢀmethylphenyl)ꢀ2ꢀ
methylsulfanylꢀ3 ꢀquinazolinꢀ4ꢀone (IX) was obtained
by dissolving compound (VIII) in 2% alcoholic sodium
hydroxide solution and methylating with dimethyl sulꢀ
phate with stirring at room temperature. Nucleophilic
Chemistry
H
Synthetic route depicted in the scheme outlines the
chemical part of the present work. The key intermediate
H
3ꢀ(2ꢀmethylphenyl)ꢀ2ꢀthioxoꢀ2,3ꢀdihydroꢀ1
linꢀ4ꢀone (VIII) was obtained by reacting aniline (
with carbon disulphide and sodium hydroxide in dimethꢀ
yl sulphoxide to give sodium dithiocarbamate, which was
methylated with dimethyl sulfate to afford the dithioꢀ with hydrazine hydrate was carried out using ethanol as
carbamic acid methyl ester (VI). Compound (VI) on a solvent to afford 3ꢀ(2ꢀmethylphenyl)ꢀ2ꢀhydrazinoꢀ
Hꢀquinazoꢀ
V)
displacement of methylthio group in compound (IX
)
Antitubercular and antibacterial activity of synthesized compounds (XIIa
–j)
Test compound (MIC in
Microorganism
µ
g/mL)
Stanꢀ
dard*
(
XIIa
)
(
XIIb
)
(
XIIc
)
(
XIId
)
(
XIIe
)
(
XIIf
)
(
XIIg
)
(
XIIh
)
(
XIIi
)
(XIIj)
M. tuberculosis
S. typhi
63
66
125
63
32
63
63
63
63
63
63
32
63
63
16
63
63
6
32
32
32
63
63
63
32
63
32
32
6
63
63
63
63
13
63
63
63
13
63
63
63
3
8
3
8
6
32
63
32
63
32
32
32
32
8
1
4
2
1
1
1
1
1
1
1
1
E. coli
125
125
125
63
8
8
S. flexneri
16
8
16
16
16
16
32
8
P. vulgaris
125
63
63
32
32
63
63
125
63
63
32
63
63
63
125
32
Enterobacter spp
K. pneumonia
S. enteritidis
B. subtilis
.
125
63
16
16
16
8
125
63
125
63
63
63
32
63
S. flexneri
63
125
125
125
125
16
16
8
P. aeruginosa
63
8
32
* Gatifloxacin was used as a reference standard against M. tuberculosis, whereas ciprofloxacin was used as a reference standard for other
bacteria.
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 42
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2016

334
ALAGARSAMY et al.
terial in IR and 1H NMR spectra of all the compounds
XIIa
). The IR and 1H NMR spectra of these comꢀ
pounds showed the presence of peaks due to thiosemiꢀ
carbazides, carbonyl (C=O), NH, and aryl groups.
The mass spectra of the title compounds showed moꢀ
lecular ion peaks corresponding to their molecular
3
Hꢀquinazolinꢀ4ꢀone (X). The long duration of reacꢀ
tion (33 h) required might be due to the presence of
bulky aromatic ring at position 3, which might have
reduced the reactivity of quinazoline ring system at
Cꢀ2 position. The title compounds 1ꢀ(3ꢀ(2ꢀmethꢀ
(
–j
ylphenyl)ꢀ4ꢀoxoꢀ3
stituted)thiosemicarbazides (XIIa
condensation of the amino group of 3ꢀ(2ꢀmethylpheꢀ
nyl)ꢀ2ꢀhydrazinoꢀ3 ꢀquinazolinꢀ4ꢀone ( ) with a variꢀ
ety of methyl esters of dithiocarbamic acid (XIa ). The
formation of title product is indicated by the disappearꢀ analysis satisfactorily confirmed elemental composiꢀ
ance of the peak due to NH and NH2 of the starting maꢀ
H
ꢀdihydroquinazolinꢀ2ꢀyl)ꢀ4ꢀ(subꢀ
–j) were obtained by
formulae. In the mass spectra of compounds (XIIa
a common peak at 144 corresponding to quinazoꢀ
linꢀ4ꢀone moiety appeared. Elemental (C, H, N)
–j),
m/z
H
X
–j
tion and purity of the synthesized compounds.
S
S−Na+
S
SCH3
CH3
C
CH3
C
CH3
NH
NH
NH2
(a)
(b)
(V
)
(VI)
(с)
H3C
COOCH3
H
H3C
O
CH3
O
NH
N
N
N
S
N
S
N
SH
H
(VIII)
(d)
H3C
O
H3C
O
H3C
O
(e)
(f)
N
N
N
N
H
H
N
N
N
SCH3
NHNH2
N
N
R
H
S
(
IX)
(X
)
(XIIa–j)
H C
3
(
XIIa
)
(XIIb
)
(
XIIc
)
(XIId
)
(XIIe)
H C
2
CH
3
OCH3
(
XIIf
)
(
XIIg
)
(XIIh
)
(
XIIi
)
(XIIj)
NO
2
OCH
CH3
Cl
3
N
Reagents and conditions: (a) CS2, NaOH, DMSO, 30 min; (b) Dimethyl sulphate, 2 h; (c) Methyl anthranilate,
Anhydrous K2CO3, EtOH reflux, 22 h; (d) 2% alcoholic sodium hydroxide solution. Dimethyl sulphate, 1 h;
(e) Hydrazine hydrate, Anhydrous potassium carbonate, Ethanol reflux, 33 h; (f) methylꢀNꢀ(substituted) dithioꢀ
carbamate, Ethanol reflux, 22–30 h.
Scheme. Synthesis of 1ꢀ(3ꢀ(2ꢀmethylphenyl)ꢀ4ꢀoxoꢀ3Hꢀquinazolinꢀ2ꢀyl)ꢀ4ꢀ(substituted)thiosemicarbazides.
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 42
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2016

ANTIMICROBIAL ACTIVITIES OF SOME SYNTHESIZED THIOSEMICARBAZIDES
335
Antitubercular Activity
These derivatives have exhibited significant antibacteriꢀ
al activity against various Gramꢀpositive and Gramꢀ
negative bacteria, including M. tuberculosis. Among the
series, compound (XIIh) showed the most potent activꢀ
ity against S. typhi, E. coli, and B. subtilis,whilethe comꢀ
pound (XIIi) showed the most potent activity against
E. coli, B. subtilis, P. aeruginosa, S. typhi, and S. flexneri.
The test compounds (XIIh) and (XIIi) exhibited the anꢀ
titubercular activity at the minimum concentration
The synthesized compounds were screened for
their in vitro antimycobacterial activity against M. tuꢀ
berculosis strain H37RV. The results are expressed in
terms of minimum inhibitory concentration (MIC).
The results of antimycobacterial activity depicted in the
Table indicate that the test compounds inhibited the
growth of Mycobacterium in varying degree. Comꢀ
pounds with aliphatic substituents showed lower antituꢀ
bercular activity over the aryl and heteroaryl substituꢀ
ents. The compounds with an electron withdrawing
substituent on the aryl ring showed better activity over
the unsubstituted or an electron donating substituent
on the aryl ring. Among the tested compounds,1ꢀ(3ꢀ
(2ꢀmethylphenyl)ꢀoxoꢀ3Hꢀquinazolinꢀ2ꢀyl)ꢀ4ꢀ(4ꢀ
chlorophenyl)thiosemicarbazide (XIIh), as well as
1ꢀ(3ꢀ(2ꢀmethylphenyl)ꢀ4ꢀoxoꢀ3Hꢀquinazolinꢀ2ꢀyl)ꢀ
4ꢀ(4ꢀnitrophenyl)ꢀthiosemicarbazide (XIIi) exhibited
the antitubercular activity at the minimum concentraꢀ
(3 μg/mL) and thus offer potential for further optimiꢀ
zation and development to new antitubercular agents.
EXPERIMENTAL
Chemistry
Melting points (mp) were taken in open capillaries
on a Thomas Hoover melting point apparatus (Thoꢀ
mas Hoover, USA) and are uncorrected. The IR specꢀ
tra (
, cm–1) were recorded in potassium bromide disks
ν
tion (3 μg/mL).
on a PerkinꢀElmer 398 spectrometer (PerkinꢀElmer,
USA). The 1H and 13C NMR spectra were recorded in
CDCl3 on a DPXꢀ300 MHz Bruker FTꢀNMR specꢀ
trometer (Bruker, USA). The chemical shifts are reꢀ
Antibacterial Activity
Among the different substituents at Cꢀ2 position of
the quinazolinꢀ2ꢀyl, aryl and heteroaryl substitutents
exhibited better activity over the aliphatic cyclic subꢀ
stituents. Compounds with electron withdrawing subꢀ
stituents like –Cl and –NO2 showed better activity over
the unsubstituted and electron donating substituents.
Compounds (XIIh) and (XIIi) emerged as the most acꢀ
tive compounds of the series. Compound (XIIh) showed
the most potent activity against S. typhi, E. coli, and
B. subtilis, while the compound (XIIi) showed the most
potent activity against E. coli, B. subtilis, P. aeruginosa,
S. typhi, and S. flexneri.
ported as parts per million ( , ppm) with tetramethylsiꢀ
δ
lane (TMS) used as an internal standard. Mass spectra
were obtained on a JEOLꢀSXꢀ102 instrument (JEOL,
Japan) using fast atom bombardment (FAB positive).
Elemental analysis was performed on a PerkinꢀElmer
2400 CHN analyzer (PerkinꢀElmer, USA) and values
were within the acceptable limits of the calculated valꢀ
ues ( 0.4%). The progress of the reaction was moniꢀ
tored on readymade silica gel plates (Merck, Norway)
using chloroform–methanol (9 : 1) as a solvent system.
Iodine was used as a developing agent. All chemicals
and reagents used in the synthesis were obtained from
Aldrich (USA), Lancaster (USA), or Spectrochem
(India) and were used without further purification.
Cytotoxicity
3ꢀ(2ꢀMethylphenyl)ꢀ2ꢀthioxoꢀ2,3ꢀdihydroꢀ1
Hꢀ
Cytotoxicity studies conducted on HeLa cells sugꢀ
gest that the studied compounds are devoid of any
signicant toxicity. The drugs at the concentration of
quinazolinꢀ4ꢀone (VIII). A solution of ꢀtoluidine (V)
o
(0.02 mol) in dimethyl sulphoxide (10 mL) was stirred
vigorously. To this mixture carbon disulphide (1.6 mL)
and 20 M aqueous sodium hydroxide (1.2 mL) were
added dropwise during 30 min with stirring. Dimethyl
sulphate (0.02 mol) was added gradually keeping the
reaction mixture stirring in freezing mixture for 2 h.
The reaction mixture was then poured into ice water.
The solid (VI) obtained was filtered, washed with waꢀ
ter, dried, and recrystallized from ethanol. Methyl
anthranilate (VII) (0.01 mol) and the above prepared
200 μg/mL were diluted to 3.25 μg/mL by serial twoꢀ
fold dilutions. Following the incubation for 48 h in a
drug, the cells were treated with methylene blue to
measure their growth/viability using a spectrophotomꢀ
eter as described previously [18]. The most potent comꢀ
pounds (XIIh) and (XIIi) did not show any toxicity
against HeLa cells even at concentrations greater than
100 μg/mL. Altogether, the results of SAR studies esꢀ
tablish the 1ꢀ(3ꢀ(2ꢀmethylphenyl)ꢀ4ꢀoxoꢀ3Hꢀquinazoꢀ
linꢀ2ꢀyl)ꢀ4ꢀ(substituted)thiosemicarbazides nucleus as
a chemical structure endowed with antimicrobial
properties.
N
ꢀ(2ꢀmethylphenyl)ꢀmethyl dithiocarbamic acid (VI)
(0.01 mol) were dissolved in ethanol (20 mL). Anhydrous
potassium carbonate (100 mg) was added to this mixture
and refluxed for 22 h. The reaction mixture was cooled in
ice and the solid separated was filtered, purified by disꢀ
solving in 10% alcoholic sodium hydroxide solution,
CONCLUSIONS
In summary, synthesis of a new series of 1ꢀ(3ꢀ(2ꢀ and reꢀprecipitated by treating with dilute hydrochloꢀ
methylphenyl)ꢀ4ꢀoxoꢀ3 ꢀdihydroquinazolinꢀ2ꢀyl)ꢀ4ꢀ ric acid. The solid obtained was filtered, washed with
(substituted)thiosemicarbazides have been described. water, dried, and recrystallized from ethanol. Yield
H
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 42
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336
ALAGARSAMY et al.
86%, mp 240–242
°
C; IR: 3211 (NH), 1686 (C=O), added simultaneously drop wise during 30 min with
1213 (C=S); 1H NMR: 2.34 (s, 3H, CH3), 7.11–7.13 m,
2H, ArꢀH), 7.39–7.41 (m, 2H, ArꢀH), 7.55–7.81 (m,
4H, ArH), 10.3 (br s, 1H, NH); 13C NMR: 12.67,
120.11, 121.79, 125.69, 126.25, 126.88, 127.23,
127.95, 132.89, 133.75, 134.98, 140.75, 145.89,
stirring. Dimethyl sulphate (0.02 mol) was added gradꢀ
ually by keeping the reaction mixture stirring in a freezꢀ
ing mixture; the stirring in a freezing mixture continued
for further 2 h. The reaction mixture was then poured
into ice water and the solid obtained was filtered,
washed with water, dried, and recrystallized from ethaꢀ
160.25, 162.89; MS (m/z
): 268 [M+]. Anal. Calcd for
C15H12N2OS: C, 67.14; H, 4.51; N, 10.44. Found: C,
67.19; H, 4.57; N, 10.38.
nol to afford methylꢀ
XIa ).
3ꢀ(2ꢀMethylphenyl)ꢀ2ꢀhydrazinoꢀ3Hꢀquinazolinꢀ4ꢀ
one (VI) (2.32 g, 0.01 mol) and appropriate methylꢀ
(substituted) dithiocarbamate (XIa ) (0.01 mol) were
Nꢀ(substituted) dithiocarbamate
(
–j
3ꢀ(2ꢀMethylphenyl)ꢀ2ꢀmethylsulfanylꢀ3
4ꢀone (IX). The 3ꢀ(2ꢀmethylphenyl)ꢀ2ꢀthioxoꢀ2,3ꢀdiꢀ
hydroꢀ1 ꢀquinazolinꢀ4ꢀone (VIII) (0.01 mol) was
Hꢀquinazolinꢀ
Nꢀ
–j
H
dissolved in ethanol and refluxed for 22–30 h (until the
methyl mercaptan evolution ceases). After completion
of the reaction the reaction mixture was cooled to room
temperature. The solid obtained was filtered, dried, and
recrystallized from ethanol. By adapting the above proceꢀ
dissolved in 40 mL of 2% alcoholic sodium hydroxide
solution. To this mixture, dimethyl sulphate (0.01 mol)
was added dropwise with stirring. The stirring was conꢀ
tinued for 1 h, the reaction mixture was then poured
into ice water. The solid obtained was filtered, washed
with water, dried, and recrystallized from ethanol–
chloroform (75 : 25) mixture. Yield 88%, mp 130–
132°
C; IR: 1685 (C=O), 1610 (C=C); 1H NMR: 2.01
(s, 3H, SCH3), 2.28 (s, 3H,CH3), 6.91–6.93 (m, 1H,
ArꢀH), 7.22–7.24 (m, 2H, ArꢀH), 7.41–7.46 (m, 4H,
ArꢀH), 7.71–7.73 (d,
NMR: 9.85, 12.73, 120.22, 121.65, 125.73, 126.55,
126.87, 127.42, 127.85, 132.65, 133.75, 134.98,
140.75, 145.89, 160.35, 162.75; MS (
): 282 [M+];
Anal. Calcd for C16H14N2OS: C, 68.06; H, 5.00; N,
9.92. Found: C, 68.24; H, 5.03; N, 9.97.
dure the compounds (XIIa
1ꢀ[3ꢀ(2ꢀMethylphenyl)ꢀ4ꢀoxoꢀ3
4ꢀ[cyclohexyl] thiosemicarbazide (XIIa). Yield 77%;
mp 250–252 C; IR: 3290 (NH), 3272 (NH), 3223
–j) were prepared.
Hꢀquinazolinꢀ2ꢀyl]ꢀ
°
1
(NH), 1656 (C=O), 1610 (C=N), 1210 (C=S); H
NMR: 1.53–1.71 (m, 6H, CH2), 1.83 (s, 2H, CH2),
1.92 (s, 2H, CH2), 2.31 (s, 2H, CH3), 2.54 (m, 1H, CH),
7.22–7.23 (m, 1H, ArH), 7.65–7.67 (m, 1H, ArH),
J
= 7.0 Hz, 1H, ArꢀH); 13C
8.43–8.48 (d,
ArH), 8.93–8.96 (d,
J
= 7.1 Hz, 2H, ArꢀH), 8.61–8.64 (m, 1H,
= 8.0 Hz, 2H, ArꢀH), 9.12–9.23
m/z
J
(m, 1H, ArH), 9.33 (s, 1H, NH), 9.56 (s, 1H, NH),
11.23 (s, 1H, NH); 13C NMR: 12.75, 22.14, 25.89,
39.89, 52.75, 120.56, 123.35, 123.68, 125.28, 127.78,
127.85, 128.61, 130.81, 131.86, 133.52, 134.12, 138.75,
158.69, 162.45, 183.74; MS (m/z
): 407 (M+, 100); Anal.
Calcd. for C22H25N5OS: C, 64.84; H, 6.18; N, 17.18;
Found: C, 64.83; H, 6.21; N, 17.23.
3ꢀ(2ꢀMethylphenyl)ꢀ2ꢀhydrazinoꢀ3
4ꢀone (X). The 3ꢀ(2ꢀmethylphenyl)ꢀ2ꢀmethylsulfaꢀ
nylꢀ3 ꢀquinazolinꢀ4ꢀone (IX) (0.01 mol) was disꢀ
Hꢀquinazolinꢀ
H
solved in ethanol (25 mL). To this mixture, hydrazine
hydrate (99%) (0.1 mol) and anhydrous potassium
carbonate (100 mg) were added and refluxed for 33 h.
The reaction mixture was cooled and poured into iceꢀ
water. The solid obtained was filtered, washed with waꢀ
ter, dried, and recrystallized from chloroform–benzene
1ꢀ[3ꢀ(2ꢀMethylphenyl)ꢀ4ꢀoxoꢀ3
4ꢀ[benzyl] thiosemicarbazide (XIIb). Yield 70%; mp
190–192 C; IR: 3327 (NH), 3310 (NH), 3237 (NH),
°C; IR: 3356, 1672 (C=O), 1610 (C=N), 1212 (C=S); H NMR:
Hꢀquinazolinꢀ2ꢀyl]ꢀ
°
1
(25 : 75) mixture. Yield 81%, mp 200–202
1
2.32 (s, 3H, CH3), 4.62 (s, 2H, CH2), 6.12–6.15 (m,
3293 (NHNH2), 1672 (C=O); H NMR: 2.31 (s, 3H,
CH3), 5.01 (s, 2H, NH2), 6.89–6.91 (m, 1H, ArꢀH),
7.21–7.23 (m, 2H, ArꢀH), 7.39–7.41 (m, 4H, ArꢀH),
2H, ArH), 6.53–6.55 (m, 1H, ArH), 7.21–7.32 (d,
J
= 7.5 Hz, 2H, ArꢀH), 7.42–7.45 (d,
ArꢀH), 7.73–7.75 (d, = 7.5 Hz, 2H, ArꢀH), 8.00–
8.01 (m, 1H, ArH), 8.05–8.07 (d, = 7.5 Hz, 2H, Arꢀ
J = 7.0 Hz, 2H,
J
7.68–7.70 (d, J = 6.5 Hz, 1H, ArꢀH), 9.63 (s, 1H, NH);
13C NMR: 12.69, 120.35, 121.77, 125.65, 126.55,
126.88, 127.23, 127.95, 132.73, 133.55, 134.15, 140.85,
J
H), 8.42–8.44 (m, 1H, ArH), 8.53 (s, 1H, NH), 8.85
(s, 1H, NH), 9.26 (s, 1H, NH); 13C NMR: 12.95, 49.68,
120.71, 123.48, 123.68, 125.28, 125.68, 126.74, 127.22,
127.78, 127.85, 128.61, 130.81, 131.86, 133.57, 134.85,
138.75, 140.35, 158.69, 162.35, 183.58; MS (m/z): 415
(M+, 100); Anal. Calcd. for C23H21N5OS: C, 66.41; H,
5.07; N, 16.83; Found: C, 66.36; H, 4.94; N, 16.81.
145.91, 160.25, 162.93; MS (m/z
): 266 (M+); Anal.
Calcd for C15H14N4O: C, 67.65; H, 5.29; N, 21.04.
Found: C, 67.58; H, 5.28; N, 21.02.
General Procedure for Synthesis
of 1ꢀ(3ꢀ(2ꢀMethylphenyl)ꢀ4ꢀOxoꢀ3ꢀPhenylꢀ3Hꢀ
Dihydroquinazolinꢀ2ꢀyl)ꢀ4ꢀ
1ꢀ[3ꢀ(2ꢀMethylphenyl
4ꢀ[phenyl] thiosemicarbazide (XIIc). Yield 73%; mp
245–247 C; IR: 3395 (NH), 3183 (NH), 3270 (NH),
1676 (C=O), 1610 (C=N), 1256 (C=S); 1H NMR: 2.41
(s, 3H, CH3), 6.59–6.60 (d, = 7.0 Hz, 1H, ArꢀH)
To this mixture, carbon disulphide (1.6 mL) and aqueꢀ 7.02–7.05 (m, 3H, ArꢀH), 7.45–7.48 (m, 3H, ArꢀH),
ous sodium hydroxide 1.2 mL (20 M solution) were 7.55–7.58 (m, 3H, ArꢀH), 7.67–7.70 (m, 3H, ArꢀH),
)ꢀ4ꢀoxoꢀ3Hꢀquinazolinꢀ2ꢀyl]ꢀ
(substituted)thiosemicarbazides (XIIa
–j)
°
A solution of primary alkyl/aryl amine (0.02 mol)
J
in dimethyl sulfoxide (10 mL) was stirred vigorously.
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ANTIMICROBIAL ACTIVITIES OF SOME SYNTHESIZED THIOSEMICARBAZIDES
337
8.01 (br s, 1H, NH), 8.7 (br s, 1H, NH), 10.22 (br s, 1H,
13
1ꢀ[3ꢀ(2ꢀMethylphenyl)ꢀ4ꢀoxoꢀ3
yl]ꢀ4ꢀ(4ꢀmethoxyphenyl) thiosemicarbazide (XIIg).
Yield 81%; mp 232–233 C; IR: 3323 (NH), 3310
Hꢀquinazolinꢀ2ꢀ
NH); C NMR: 12.77, 120.68, 123.55, 123.74 125.18,
125.36, 126.74, 127.22, 127.78, 127.85, 128.61, 130.81,
131.86, 133.75, 134.25, 138.75, 140.35, 158.69, 162.75,
°
(NH), 3242 (NH), 1691 (C=O), 1605 (C=N), 1286
1
183.75; MS (m/z
): 401 (M+, 100); Anal. Calcd. for
C22H19N5OS:C, 65.81; H, 4.77; N, 17.44; Found: C,
65.82; H, 4.73; N, 17.38.
(OCH3), 1210 (C=S); HNMR : 2.32 (s, 3H, CH3),
3.69 (s, 3H, OCH3), 6.51 (br s, 1H, NH), 6.55–6.57
(m, 1H, ArꢀH), 6.86–6.88 (m, 1H, ArꢀH), 7.24–7.29
(d,
2H, ArꢀH), 7.42–7.46 (d,
7.88–7.91 (m, 1H, ArꢀH), 8.14–8.17 (d,
J
= 7.3 Hz, 2H, ArꢀH), 7.32–7.36 (d,
= 7.2 Hz, 2H, ArꢀH),
= 7.5 Hz,
J = 7.5 Hz,
1ꢀ[3ꢀ(2ꢀMethylphenyl)ꢀ4ꢀoxoꢀ3
4ꢀ[2ꢀmethylphenyl] thiosemicarbazide (XIId). Yield
81%; mp 245–247 C; IR: 3407 (NH), 3381 (NH),
Hꢀquinazolinꢀ2ꢀyl]ꢀ
J
J
°
2H, ArꢀH), 8.24–8.27 (m, 1H, ArꢀH), 8.84 (br s, 1H,
NH), 10.82 (br s, 1H, NH); 13C NMR: 12.75, 53.75,
120.61, 123.85, 123.98, 125.42, 125.87, 126.74, 127.22,
127.78, 127.85, 128.35, 128.61, 130.81, 131.86, 133.58,
138.75, 140.45, 156.79, 162.59, 181.61; MS (m/z): 431
(M+, 100); Anal. Calcd. for C23H21N5O2S: C, 64.02; H,
4.91; N, 16.23; Found: C, 64.01; H, 4.94; N, 16.28.
3265 (NH), 1676 (C=O), 1650 (C=N), 1257 (C=S);
1H NMR: 2.33 (s, 6H, CH3), 6.85 (br s, 1H, NH),
6.82–6.84 (m, 1H, ArH), 7.04–7.06 (m, 1H, ArH),
7.27–7.31 (d,
= 7.2 Hz, 2H, ArꢀH), 7.83–7.87 (d,
ArꢀH), 7.91–7.94 (m, 1H, ArH), 7.99–8.01 (d,
J
= 7.0 Hz, 2H, ArꢀH), 7.62–7.66 (d,
J
J
= 7.0 Hz, 2H,
J
= 7.0 Hz, 2H, ArꢀH), 8.51–8.53 (m, 1H, ArH), 8.72
1ꢀ[3ꢀ(2ꢀMethylphenyl)ꢀ4ꢀoxoꢀ3
4ꢀ[4ꢀchlorophenyl] thiosemicarbazide (XIIh). Yield
80%; mp 245–247 C; IR: 3330 (NH), 3281 (NH),
Hꢀquinazolinꢀ2ꢀyl]ꢀ
(br s, 1H, NH), 10.21 (br s, 1H, NH); 13C NMR: 12.58,
12.61, 120.68, 123.55, 123.74, 125.18, 125.36, 126.74,
127.22, 127.78, 127.85, 128.61, 128.95, 130.81, 131.86,
133.54, 134.25, 138.75, 138.85, 140.35, 158.69, 162.75,
°
3218 (NH), 1675 (C=O), 1615 (C=N), 1210 (C=S);
1H NMR: 2.31 (s, 3H, CH3), 6.61–6.64 (m, 1H, ArꢀH),
181.75;MS (m/z
): 415 (M+, 100); Anal. Calcd. for
C23H21N5OS:C, 66.48; H, 5.09; N, 16.85; Found: C,
66.53; H, 5.12; N, 16.86.
7.04–7.07 (d,
= 7.5 Hz, 2H, ArꢀH), 7.90–7.93 (d,
ArꢀH), 7.94–7.97 (m, 1H, ArꢀH), 7.91–7.96 (d,
J
= 7.5 Hz, 2H, ArꢀH), 7.10–7.13 (d,
J
J
= 7.2 Hz, 2H,
J
= 7.0 Hz, 2H, ArꢀH), 7.97–7.99 (m, 1H, ArꢀH),
1ꢀ[3ꢀ(2ꢀMethylphenyl)ꢀ4ꢀoxoꢀ3
4ꢀ[4ꢀmethylphenyl] thiosemicarbazide (XIIe). Yield
80%; mp 240–242 C; IR: 3407 (NH), 3243 (NH),
3200 (NH), 1676 (C=O), 1180 (C=N), 1256 (C=S);
1H NMR: 2.27 (s, 3H, CH3), 2.37 (s, 3H, CH3), 5.95
Hꢀquinazolinꢀ2ꢀyl]ꢀ
9.42 (br s, 1H, NH), 10.33 (br s, 1H, NH); 13C NMR:
12.75, 120.45, 123.77, 123.89, 125.23, 125.87, 126.81,
127.09, 127.58, 128.34, 127.99, 128.61, 130.81, 133.57,
131.86, 138.75, 140.45, 156.79, 162.59, 181.61; MS
°
(m/z
): 435 (M+, 100); Anal. Calcd. for C22H18ClN5OS:
(br s, 1H, NH), 6.96–6.98 (d, J = 7.0 Hz, 1H, ArꢀH),
C, 60.47; H, 4.12; N, 16.01; Found: C, 60.48; H, 4.16;
N, 16.08.
1ꢀ[3ꢀ(2ꢀMethylphenyl)ꢀ4ꢀoxoꢀ3
4ꢀ[4ꢀnitrophenyl]thiosemicarbazide (XIIi). Yield 74%;
mp 233–235 C; IR: 3321 (NH), 3310 (NH), 3226
(NH), 1688 (C=O), 1604 (C=N), 1208 (C=S); H
NMR: 2.11 (s, 3H, CH3), 6.53–6.56 (m, 1H, ArH),
6.70–6.72 (m, 1H, ArH), 7.05–7.09 (d, = 8.1 Hz,
2H, ArꢀH), 7.10–7.13 (d, = 8.1 Hz, 2H, ArꢀH),
7.32–7.36 (d, = 7.3 Hz, 2H, ArꢀH), 7.63–7.66 (m,
1H, ArꢀH), 7.88–7.93 (d, = 7.3 Hz, 2H, ArꢀH),
7.08–7.12 (m, 3H, ArꢀH), 7.32–7.36 (m, 4H, ArꢀH),
7.45–7.47 (m, 4H, ArꢀH), 8.06 (br s, 1H, NH), 10.53
(br s, 1H, NH); 13C NMR: 12.98, 23.85, 120.52, 123.71,
123.84, 125.42, 125.87, 126.74, 127.22, 127.78, 127.85,
128.61, 130.81, 131.86, 133.25, 134.11, 138.75, 140.45,
H
ꢀquinazolinꢀ2ꢀyl]ꢀ
°
1
158.69, 162.59, 183.61; MS (m/z
): 415 ([M + H]+, 100);
Anal. Calcd. for C23H21N5OS: C, 66.48; H, 5.09; N,
16.85; Found: C, 66.52; H, 5.10; N, 16.89.
J
J
1ꢀ[3ꢀ(2ꢀMethylphenyl)ꢀ4ꢀoxoꢀ3
4ꢀ(3ꢀmethoxyphenyl) thiosemicarbazide (XIIf). Yield
80%; mp 210–212 C; IR: 3407 (NH), 3280 (NH),
Hꢀquinazolinꢀ2ꢀyl]ꢀ
J
J
°
7.95–7.98 (m, 1H, ArꢀH), 8.81 (br s, 1H, NH), 8.96
(br s, 1H, NH), 10.21 (br s, 1H, NH); 13C NMR: 12.83,
120.39, 123.47, 123.84, 125.42, 125.87, 126.74, 127.22,
127.78, 127.85, 128.35, 128.61, 130.81, 131.66, 133.87,
3205 (NH), 1677 (C=O), 1620 (C=N), 1280 (OCH3),
1260 (C=S); 1H NMR: 2.32 (s, 3H, CH3), 3.69 (s, 3H,
OCH3), 6.72 (br s, 1H, NH), 7.10–7.12 (m, 1H, ArꢀH),
138.75, 139.45, 158.69, 161.79, 181.61; MS (m/z): 446
7.32–7.35 (m, 1H, ArꢀH), 7.39–7.42 (d,
ArꢀH), 7.49–7.54 (d, = 7.80 Hz, 2H, ArꢀH), 7.63–
7.69 (d, = 7.2 Hz, 2H, ArꢀH), 7.71–7.73 (m, 1H, ArꢀH),
7.82–7.84 (d, = 7.0 Hz, 2H, ArꢀH), 8.03–8.05 (m, 1H,
J = 7.5 Hz, 2H,
([M+H]+,100); Anal. Calcd. for C22H18N6O3S: C,
59.02; H, 4.02; N, 18.83; Found: C, 59.00; H, 4.04; N,
18.84.
J
J
J
13
ArH), 8.72 (br s, 1H, NH), 10.21 (br s, 1H, NH); C
NMR: 12.39, 53.85, 108.75, 109.87, 117.85, 120.48,
123.51, 123.25, 125.42, 127.53, 127.85, 128.61, 129.57,
129.99, 130.81, 131.86, 134.35, 137.57, 138.75, 158.69,
1ꢀ[3ꢀ(2ꢀMethylphenyl)ꢀ4ꢀoxoꢀ3
4ꢀ[pyridineꢀ2ꢀyl]thiosemicarbazide (XIIj). Yield 80%;
mp 210–212 C; IR: 3387 (NH), 3342 (NH), 3203
(NH), 1665 (C=O), 1610 (C=N), 1254 (C=S); H
NMR: 2.28 (s, 3H, CH3), 6.54–6.58 (m, 1H, ArH),
7.02–7.06 (m, 1H, ArH), 7.20–7.23 (d, = 7.5 Hz, 2H,
ArꢀH), 7.35–7.38 (d, = 8.1 Hz, 2H, ArꢀH), 7.41–7.45
Hꢀquinazolinꢀ2ꢀyl]ꢀ
°
1
160.15, 162.42, 179.53; MS (m/z
): 431 (M+, 100); Anal.
Calcd. for C23H21N5O2S: C, 64.02; H, 4.91; N, 16.23;
Found: C, 64.03; H, 4.87; N, 16.33.
J
J
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 42
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2016

338
ALAGARSAMY et al.
(d,
J
= 7.3 Hz, 2H, ArꢀH), 7.53–7.58 (m, 1H, ArH), incubated for 48 h without the test substances. The soluꢀ
7.71–7.74 (d, J = 7.3 Hz, 2H, ArꢀH), 7.92–7.96 (m, 1H, tions of the compounds of the corresponding concentraꢀ
ArH), 8.72 (s, 1H, NH), 8.92 (br s, 1H, NH), 10.51 (br s, tions were applied carefully on the monolayers of HeLa
1H, NH); 13C NMR: 12.83, 108.75, 112.89, 120.48,
123.51, 123.25, 125.42, 127.53, 127.85, 128.35, 128.61,
130.81, 131.86, 134.25, 137.89, 138.75, 147.75, 157.85,
cells after the preincubation time. The monolayers of the
adherent HeLa cells were fixed by glutaraldehyde and
stained with a 0.05% solution of methylene blue for
15 min. After gently washing, the stain was eluted by
0.2 mL of 0.33 N HCl in the wells. The optical densities
were measured at 630 nm in a micro plate reader. In genꢀ
eral, compounds showed no significant cytotoxic effect
at tested concentration [18].
158.69, 161.78, 181.25; MS (m/z
): 402 ([M + H]+, 100);
Anal. Calcd. for C21H18N6OS:C, 62.53; H, 4.45; N,
21.03; Found: C, 62.50; H, 4.43; N, 21.06.
Pharmacology
Antibacterial activity. Antibacterial activity was evalꢀ
uated by agar dilution method [9, 10]. The standard
strains were procured from the American Type Culture
Collection (ATCC), Rockville, USA, and the pathologꢀ
ical strains were procured from the Department of Miꢀ
crobiology, MNR Medical College, Sangareddy, India.
The antibacterial activity of the synthesized compounds
was screened against the following bacterial strains:
P. vulgaris ATCC 9484, S. typhimurium ATCC 33068,
K. pneumoniae ATCC 13883, E. tarda, P. aeruginosa
COMPETING INTERESTS
The authors declare that they have no competing
interests.
ACKNOWLEDGMENTS
The authors gratefully acknowledge the Central
Instrumentation Facility, IIT Chennai, India, for the
spectral analysis of the compounds used in this study;
Dr. D. Sriram, Birla Institute of Technology and Sciꢀ
ences, Hyderabad campus for performing antituberꢀ
cular screening of the test compounds.
ATCC 2853, B. subtilis ATCC 6051, and S. paratyphi
All bacteria were grown on Muller–Hinton Agar (Hiꢀ
media) plates (37 C, 24 h) and the minimum inhibitory
.
°
concentration (MIC) was considered to be the lowest
concentration that completely inhibited the growth on
agar plates, disregarding a single colony or faint haze
caused by the inoculums [19, 20]. The MIC of the test
compounds was compared with the reference drug
ciprofloxacin. The values calculated from at least three
different experiments in duplicateare presentedin the
table.
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