Vol.4, No.4 (2011), 736-743
ISSN: 0974-1496
CODEN: RJCABP
http://www.rasayanjournal.com
SYNTHESIS AND ANTIBACTERIAL ACTIVITY OF SOME
NOVEL 1-(4-OXO-3-BUTYL-3H-QUINAZOLIN-2-YL)-4(SUBSTITUTED) THIOSEMICARBAZIDES
V. Alagarsamy * and P. Parthiban
Medicinal Chemistry Research Laboratory, MNR College of Pharmacy, Sangareddy,
Gr. Hyderabad -502 294, A.P. India.
*E-mail: drvalagarsamy@gmail.com
ABSTRACT
A new series of novel 1-(4-oxo-3-butyl-3H-quinazolin-2-yl)-4-(substituted) thiosemicarbazides were synthesized by
the reaction of 3-butyl-2-hydrazino quinazolin-4(3H)-one with various methyl esters of dithiocarbamic acid. The
starting material 3-butyl-2-hydrazino quinazolin-4(3H)-one was synthesized from butyl amine. When tested for their
in vitro antitubercular activity using H37RV strain on Middle brook 7H11 agar slants with OADC growth
supplement, all the test compounds inhibited the growth of Mycobacterium tuberculosis at micro gram
concentration. Among the test compounds, 1-(4-oxo-3-butyl-3,4-dihydroquinazolin-2-yl)-4-(2-nitrophenyl)
thiosemicarbazide (AS6), 1-(4-oxo-3-butyl-3,4-dihydroquinazolin-2yl)-4-(4-chlorophenyl) thiosemicarbazide (AS7)
and 1-(4-oxo-3-butyl-3,4-dihydroquinazolin-2-yl)-4-(2-pyridyl) thiosemicarbazide (AS8) are found to be the most
active compounds against M.tuberculosis with the MIC of 6 µg/ml. The title compounds are also screened for the
antimicrobial activity against some other gram positive and gram negative bacteria by agar dilution method,
compounds AS6 and AS7 showed the most potent activity (MIC in the range of 32-63 µg/ml) against the tested
bacteria.
Key words: Antitubercular, Quinazolinone, Thiosemicarbazide, Anti-bacterial, M. tuberculosis
© 2011 RASĀYAN. All rights reserved.
INTRODUCTION
Tuberculosis remains the most important communicable disease in the world1. Tuberculosis (TB) is an
infection, primarily in the lungs (a pneumonia), caused by bacteria called Mycobacterium tuberculosis2.
Along with the recent increase in cases of tuberculosis, there is a progressive increase in multidrug
resistant (MDR) tuberculosis. Some of the MDR isolates are resistant to as many as seven of the
commonly employed antimycobacterial drugs3. 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, 3-substituted quinazolines are interesting4.
Literature survey indicates that the quinazoline nucleus substituted at 2,3-position showed significant
antitubercular activity5-7. The presence of the functional moiety like thiosemicarbazides and
Thiosemicarbazones in different heterocyclic moiety also found to exhibit the antitubercular activity8.
Hence the pharmacophore containing quinazolines ring attached with thiosemicarbazides9 or
thiosemicarbazones10-12 are expected to possess more pronounce antitubercular and antimicrobial
activities13-16. With this aim, in the present study, we have placed the thiosemicarbazides moiety at the C2 position of quinazoline ring and studied their antitubercular and other antimicrobial activity against
different gram positive and negative bacteria.
EXPERIMENTAL
Melting points (mp) were taken in open capillaries on Thomas Hoover melting point apparatus and are
uncorrected. The IR spectra were recorded in film or in potassium bromide disks on a Perkin-Elmer 398
spectrometer. The 1H NMR spectra were recorded on a DPX-500 MHz Bruker FT-NMR spectrometer.
The chemical shifts were reported as parts per million (δ ppm) tetramethylsilane (TMS) as an internal
SOME NOVEL THIOSEMICARBAZIDES
V. Alagarsamy and P. Parthiban
Vol.4, No.4(2011), 736-743
standard. Mass spectra were obtained on a JEOL-SX-102 instrument using fast atom bombardment (FAB
positive). Elemental analysis was performed on a Perkin-Elmer 2400 C, H, N analyzer and values were
within the acceptable limits of the calculated values. The progress of the reaction was monitored on
readymade silica gel plates (Merck) using chloroform-methanol (9:1) as a solvent system. Iodine was
used as a developing agent. Spectral data (IR, NMR and mass spectra) confirmed the structures of the
synthesized compounds and the purity of these compounds was ascertained by microanalysis. Elemental
(C, H, N) analysis indicated that the calculated and observed values were within the acceptable limits (±
0.4%). All chemicals and reagents were obtained from Aldrich (USA), Lancaster (UK) or Spectrochem
Pvt.Ltd (India) and were used without further purification.
Synthesis of 3-butyl-2-thioxo quinazolin-4(3H)-one (4)
A solution of butyl amine (1) (0.02 mol) in dimethyl sulfoxide (10ml) was stirred vigorously. To
this was added carbon disulphide (1.6ml) and aqueous sodium hydroxide (1.2ml) (20 molar solutions)
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 obtained was filtered, washed with water, dried and recrystallized from ethanol. Methyl
anthranilate (3) (0.01 mol) and the above prepared N-(butyl)-methyl dithiocarbamic acid (2) (0.01 mol),
were dissolved in ethanol (20ml). To this anhydrous potassium carbonate (100 mg) was added and
refluxed for 22 h. The reaction mixture was cooled in ice and the solid separated was filtered and purified
by dissolving in 10% alcoholic sodium hydroxide solution and reprecipitated by treating with dilute
hydrochloric acid. The solid obtained was filtered, washed with water, dried and recrystallized from
ethanol.
Synthesis of 3-Butyl-2-methylsulfanyl quinazolin-4(3H)-one (5)
The 3-butyl-2-thioxo quinazolin-4(3H)-one (4) (0.01 mol) was dissolved in 40 ml of 2%
alcoholic sodium hydroxide solution. To this dimethyl sulphate (0.01 mol) was added drop wise with
stirring. The stirring was continued 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.
Synthesis of 3-Butyl-2-hydrazino quinazolin-4(3H)-one (6)
The 3-butyl-2-methylsulfanyl quinazolin-4(3H)-one (5) (0.01 mol) was dissolved in ethanol
(25ml). To this hydrazine hydrate (99%) (0.1 mol) and anhydrous potassium carbonate (100 mg) was
added and refluxed for 30 h. The reaction mixture was cooled and poured into ice-water. The solid so
obtained was filtered, washed with water, dried and recrystallized from chloroform-benzene (25:75)
mixture.
General procedure for Synthesis of 1-(4-oxo-3-butyl-3H-dihydroquinazolin-2-yl)-4-(substituted)
thiosemicarbazides (AS1-AS10)
A solution of primary Alkyl/Aryl amine (0.02 mol) in dimethyl sulfoxide (10ml) was stirred
vigorously. To this simultaneously carbon disulphide (1.6ml) and aqueous sodium hydroxide 1.2ml (20ml
solution) was added drop wise during 30min with stirring. Dimethyl sulphate (0.02 mol) was added
gradually by keeping the reaction mixture stirring in a freezing mixture and 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 ethanol.
3-Butyl-2-hydrazino-3H-quinazolin-4-one (6) (2.32 gm; 0.01 mole) Methyl N-(substituted)
dithiocarbamate (7) (0.01 mol) was dissolved in ethanol and refluxed for 24-30 h (until the methyl
mercapton evolution ceases). After completion of the reaction the reaction mixture cooled to room
temperature. The solid obtained was filtered, dried and recrystallized from ethanol. By adapting the above
procedure the compounds AS1-AS10 were prepared.
Pharmacology
In vitro antibacterial activity17-18
Evaluation of antibacterial activity done by the agar dilution method. The microorganisms used
were procured from Department of Microbiology, MNR medical college. All bacteria were grown on
SOME NOVEL THIOSEMICARBAZIDES
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V. Alagarsamy and P. Parthiban
Vol.4, No.4(2011), 736-743
Muller-Hinton agar (Hi-media) plates (37oC, 24 h). The minimum inhibitory concentration (MIC) was
considered to be the lowest concentration that completely inhibited the growth of bacteria.
In vitro M. tuberculosis Activity19-21 (Agar Dilution Method)
10 fold serial dilutions of each test compound/drug were incorporated into Middle brook 7H11
agar slants with OADC Growth Supplement. Inoculums of M. tuberculosis H37Rv were prepared from
fresh Middle brook 7H11 agar slants with OADC Growth Supplement adjusted to 1mg/mL (wet weight)
in Tween 80 (0.05%) saline diluted to 10-2 to give a concentrate of approximately 107 cfu/mL. A 5µL
amount of bacterial suspension was spotted into 7H11 agar tubes containing 10-fold serial dilutions of
drug per mL. The tubes were incubated at 37ºC, and final readings were recorded after 28 days. Tubes
having the compounds were compared with control tubes where medium alone was incubated with
H37RV. The concentration at which complete inhibition of colonies occurred was taken as active
concentration of test compound. The minimum inhibitory concentration (MIC) is defined as the minimum
concentration of compound required to give complete inhibition of bacterial growth.
RESULTS AND DISCUSSION
Synthetic route depicted in Scheme 1 outline the chemistry part of the present work. The key intermediate
3-butyl-2-thioxo quinazolin-4(3H)-one (4) was obtained by reacting butyl amine (1) with carbon
disulphide and sodium hydroxide in dimethyl sulphoxide to give sodium dithiocarbamate, which was
methylated with dimethyl sulphate to afford the dithiocarbamic acid methyl ester (2). Compound 2 on
reflux with methyl anthranilate (3) in ethanol yielded the desired 3-butyl-2-thioxo quinazolin-4(3H)-one
(4) via the thiourea intermediate in good yield (86%). It was confirmed by IR spectra of 4, which showed
intense peaks at 3250 cm-1 for cyclic thio urea (NH), 1669 cm-1 for carbonyl (C=O) and 1217 cm-1 for
thioxo (C=S) stretching. 1H NMR spectra of compound 4 showed multiplet around at δ 0.97-4.55 ppm
due to butyl group, a multiplet around δ 7.26 ppm for aromatic (4H) protons and a singlet at δ 10.5 ppm
indicating the presence of NH. Data from the elemental analyses have been found to be in conformity
with the assigned structure. Furthermore the molecular ion recorded in the mass spectra is also in
agreement with the molecular weight of the compound.
The 3-butyl-2-methysulfanyl-3H-quinazolin-4-one (5) was obtained by dissolving 4 in 2%
alcoholic sodium hydroxide solution and methylating with dimethyl sulphate with stirring at room
temperature. The IR spectra of 5 showed disappearance of NH and C=S stretching signals of cyclic
thiourea. It showed a peak for carbonyl (C=O) stretching at 1680 cm-1. The 1H NMR spectra of compound
5 showed singlet at δ 2.65 due to SCH3 ppm; and multiplet around δ 0.90-4.15 ppm and δ 7.33-7.69 ppm
was observed for butyl group and aromatic (4H) protons respectively. Data from the elemental analysis
and molecular ion recorded in the mass spectra further confirmed the assigned structure.
Nucleophilic displacement of the methylthio group of 5 with hydrazine hydrate was carried out
using ethanol as solvent to afford 3-butyl-2-hydrazino-3H-quinazolin-4(3H)-one (6). The long duration of
reaction (30 h) required might be due to the presence of bulky aromatic ring at position 3, which might
have reduced the reactivity of quinazolines ring system at C-2 position. The formation of compound 6
was confirmed by the presence of NH and NH2 signals at 3434 and 3200 cm-1 in the IR spectra. It also
showed a peak for carbonyl (C=O) at 1656 cm-1. The 1H NMR spectra of the compound 6 showed
multiplet around δ 1.37 to 4.13 and δ 4.61 ppm and 10.24 ppm due to NH2 and NH respectively, a
multiplet at δ 7.10-7.23 ppm was observed for aromatic (4H) protons. Elemental analyses data and mass
spectral data is also in agreement with the assigned structure of the compound.
The
title
compounds
1-(4-oxo-3-butyl-3H-dihydroquinazolin-2-yl)-4-(substituted)
thiosemicarbazides (AS1-AS10) were obtained by the condensation of amino group of 3-butyl-2hydrazino quinazolin-4(3H)-one (6) with a variety of methyl ester of dithiocarbamic esters. The formation
of title product is indicated by the disappearance of peak due to NH, NH2 of the starting material in IR
and 1H NMR spectrum of all the compounds AS1-AS10. The IR and 1H NMR spectrum of these
compounds showed the presence of peaks due to thiosemicarbazides, carbonyl (C=O), NH and Aryl
groups. The mass spectra of the title compounds showed molecular ion peaks corresponding to their
molecular formula. In mass spectrum of compounds AS1-AS10 a common peak at m/z 144 corresponding
SOME NOVEL THIOSEMICARBAZIDES
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Vol.4, No.4(2011), 736-743
to quinazolin-4-one moiety appeared. Elemental (C, H, N) analysis satisfactorily confirmed elemental
composition and purity of the synthesized compounds.
3-Butyl-2-thioxo quinazolin-4(3H)-one (4)
Yield = 86 %; mp 240-242 0C; IR (KBr) cm-1: 3250 (NH), 1669 (C=O), 1217 (C=S); 1H NMR
(CDCl3): δ 0.97-1.02 (t, 3H, CH3), 1.40-1.52 (m, 2H, CH2), 1.74-1.80 (m, 2H, CH2), 4.50-4.55 (m, 2H,
CH2). 7.26-7.63 (m, 4H, ArH) and 10.5 (s, 1H, NH); MS (m/z) 234 (M+); Anal. Calcd for C12H14N2OS: C,
61.51; H, 6.02; N, 11.96. Found: C, 61.55; H, 6.05; N, 11.99.
3-Butyl-2-methylsulfanyl quinazolin-4(3H)-one (5)
Yield= 88 %; mp 170-172 °C; IR (KBr) cm-1: 1680 (C=O); 1H NMR (CDCl3): δ 0.96-1.01 (t, 3H,
CH3), 1.39-1.51 (m, 2H, CH2), 1.73-1.77 (m, 2H, CH2), 2.65 (t, 3H, SCH3), 4.10-4.15 (m, 2H, CH2), 7.337.69 (m, 4H ArH); MS (m/z) 248 (M+); Anal. Calcd for C13H16N2OS: C, 62.87; H, 6.49; N, 11.28. Found:
C, 62.85; H, 6.52; N, 11.25.
3-Butyl-2-hydrazino quinazolin-4(3H)-one (6)
Yield= 81%; mp 180-182 °C; IR (KBr) cm-1: 3434 & 3200 (NHNH2), 1656 (C=O); 1H NMR
(CDCl3): δ 0.96-1.01 (t, 3H, CH3), 1.37-1.50 (m, 2H, CH2), 1.66-1.74 (m, 2H, CH2), 4.04-4.13 (m, 2H,
CH2), 4.61 (s, 2H, NH2), 7.10-7.23 (m, 4H, ArH), 10.24 (s, 1H, NH); MS (m/z) 232 (M+); Anal. Calcd for
C12H16N4O: C, 62.05; H, 6.94; N, 24.12. Found: C, 62.10; H, 6.96; N, 24.10.
1-(4-oxo-3-butyl-3H-quinazolin-2-yl)-4-(phenyl) thiosemicarbazide (AS1)
Yield: 88 %; mp: 115-117 ˚C; IR (KBr) cm-1: 3300 (NH), 3240 (NH), 1674 (C=O), 1252 (C=S);
1
H NMR (300 CDCl3) δ: 1.04-1.09 (t, 3H, CH3), 1.40-1.47 (m, 2H, CH2), 1.55-1.77 (m, 2H, CH2), 4.144.19 (m, 2H, CH2), 6.84-6.87 (d, 2H, Ar-H), 7.08 (br, s, 1H, NH), 7.36 (br s, 1H, NH), 7.43-7.53 (m, 4H,
Ar-H), 8.02-8.08 (m, 2H, Ar-H), 8.15-8.19 (d, 1H, Ar-H) 8.77 (br s, 1H, NH); MS (m/z) 367 [M+], 368
[M++1]; Anal. Calcd for C19H21N5OS: C, C, 62.10; H, 5.76; N, 19.06; Found: C, 62.13; H, 5.74; N, 19.01.
1-(4-oxo-3-butyl-3H-quinazolin-2-yl)-4-(2-methyl phenyl) thiosemicarbazide (AS2)
Yield: 73 %; mp: 100-102 ˚C; IR (KBr) cm-1: 3300 (NH), 3220 (NH), 1673 (C=O), 1254 (C=O);
1
H NMR (CDCl3): δ 1.05-1.09 (t, 3H, CH3), 1.42-1.55 (m, 2H, CH2), 1.67-1.82 (m, 2H, CH2), 2.46 (s, 3H,
CH3), 4.14-4.19 (m, 2H, CH2), 6.84-6.86 (d, 1H, Ar-H), 7.06-7.34 (m, 6H, Ar-H), 7.53 (br, s, 1H, NH),
8.03-8.08 (d,1H, Ar-H), 8.77 (br s, 1H, NH), 11.78 (br s, 1H, NH); MS (m/z): 381 [M+]; Anal. Calcd for
C20H23N5OS: C, 62.97; H, 6.08; N, 18.36; Found: C, 62.96; H, 6.11; N, 18.38.
1-(4-oxo-3-butyl-3H - quinazolin-2-yl)-4-(3-methylphenyl) thiosemicarbazide (AS3)
Yield: 81 %; mp: 195-197˚C; IR (KBr) cm-1: 3383 (NH), 3240 (NH), 1673 (C=O), 1233 (C=S);
1
H NMR (CDCl3): δ 0.92-0.99 (t, 3H, CH3), 1.31-1.40 (m, 2H, CH2), 1.83-1.89 (m, 2H, CH2), 2.13 (s, 3H,
CH3), 4.02-4.09 (m, 2H, CH2), 7.15-7.20 (d, 1H, Ar-H), 7.35-7.42 (m, 6H, Ar-H), 7.92-7.98 (d, 1H, ArH), 8.05 (br s, 1H, NH), 8.49 (br s, 1H, NH), 10.11 (br s, 1H, NH); MS (m/z): 381 [M+]; Anal. Calcd for
C20H23N5OS: C, 62.97; H, 6.08; N, 18.36; Found: C, 62.99; H, 6.05; N, 18.34.
1-(4-oxo-3-butyl-3H-quinazolin-2-yl)-4-(4-methylphenyl) thiosemicarbazide (AS4) Yield:
74%;
mp: 110-112 ˚C; IR (KBr) cm-1 : 3405 (NH), 3238 (NH), 1673 (C=O), 1253 (C=S); 1H NMR (CDCl3): δ
1.13-1.17 (t, 3H, CH3), 1.53-1.57 (m, 2H, CH2), 1.72-1.78 (m, 2H, CH2), 2.71 (s, 3H, CH3), 4.17-4.21 (m,
2H, CH2), 7.03-7.06 (d, 1H, Ar-H), 7.72-7.83 (m, 6H, Ar-H), 7.93-7.99 (d, 1H, Ar-H), 8.29 (br, s, 1H,
NH), 9.12 (br s, 1H, NH), 10.48 (br s, 1H, NH); MS (m/z) : 381; Anal. Calcd for C20H23N5OS: C, 62.97;
H, 6.08; N, 18.36; Found: C, 62.99; H, 6.06; N, 18.30.
1-(4-oxo-3-butyl-3H - quinazolin-2-yl)-4-(3-methoxy phenyl) thiosemicarbazide (AS5)
Yield: 80 %; mp: 120-122 ˚C; IR (KBr) cm-1: 3365 (NH), 3221 (NH), 1634 (C=O), 1254 (C=S);
1
H NMR (CDCl3): δ 1.05-1.11 (t, 3H, CH3), 1.55-1.61 (m, 2H, CH2), 1.59-1.67 (m, 2H, CH2), 2.32 (s, 3H,
OCH3), 3.72-3.76 (m, 2H, CH2), 7.22-7.23 (d, 1H, Ar-H), 7.48-7.55 (m, 6H, Ar-H), 7.73-7.74 (d, 1H, ArH), 8.20 (br s, 1H, NH), 8.25 (br s, 1H, NH), 10.13 (br s, 1H, NH); MS (m/z): 397 [M+]; Anal. Calcd for
C20H23N5O2S: C, 60.43; H, 5.83; N, 17.67; Found: C, 60.49; H, 5.87; N, 17.67.
SOME NOVEL THIOSEMICARBAZIDES
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V. Alagarsamy and P. Parthiban
Vol.4, No.4(2011), 736-743
CH3CH2CH2CH2NH2
+
CS2
+
DMSO
NaOH
S
CH3CH2CH2CH2NH C
S-Na+
(1)
(CH3)2SO4
O
O
NH
OCH3
EtOH
OCH3
NH CH2CH2CH2CH3
+
CH3CH2CH2CH2NH C
NH2
-CH3SH
S
N
CH2CH2CH2CH3
NaoH/EtoH
N
SCH3
(5)
EtOH
NH2NH2.H2O
O
N
S
NH NH C NH R
R
NH
S
C
(7)
-CH3SH
O
EtOH
N CH2CH2CH2CH3
N
CH2CH2CH2CH3
N
(CH3)2SO4
N S
H
(4)
SCH3
(2)
(3)
O
O
S
CH2CH2CH2CH3
N NHNH2
SCH3
(6)
AS1-AS10
H3 C
AS1
OCH3
CH3
AS2
AS3
CH3
AS4
AS5
O2 N
AS6
AS7
Cl
AS9
AS8
N
CH2
AS10
Scheme-1: Synthesis of 1-(4-oxo-3-butyl-3H-quinazolin-2-yl)-4-(substituted) Thiosemicarbazides
1-(4-oxo-3-butyl-3H-quinazolin-2-yl)-4-(2-nitrophenyl) thiosemicarbazide (AS6)
Yield: 70 %; mp: 115-117 ˚C; IR (KBr) cm-1: 3340 (NH), 3239 (NH), 1651 (C=O), 1233 (C=S);
1
H NMR (CDCl3): δ 0.90-0.96 (t, 3H, CH3), 1.53-1.61 (m, 2H, CH2), 1.86-1.91 (m, 2H, CH2), 3.63-3.68
(m, 2H, CH2), 7.19-7.21 (d, 1H, Ar-H), 7.31-7.45 (m, 6H, Ar-H), 7.72-7.73 (d, 1H, Ar-H), 8.05 (br s, 1H,
NH), 8.26 (br s, 1H, NH), 10.43 (br s, 1H, NH); MS (m/z): 412; Anal. Calcd for C19H20N6O3S: C, 55.33;
H, 4.89; N, 20.38; Found: C, 55.31; H, 4.92; N, 20.41.
1-(4-oxo-3-butyl-3H-quinazolin-2-yl)-4-(4-chlorophenyl) thiosemicarbazide (AS7)
Yield: 77 %; mp: 130-132 ˚C; IR (KBr) cm-1: 3380 (NH), 3221 (NH), 1651(C=O), 1272 (C=S);
1
H NMR (CDCl3): δ 1.04-1.09 (t, 3H, CH3), 1.49-1.52 (m, 2H, CH2), 1.74-1.79 (s, 1H, CH2), 4.14-4.19
(m, 2H, CH2), 6.99-7.02 (d, 1H, Ar-H), 7.05-7.10 (m, 2H, Ar-H), 7.26-7.38 (m, 2H, Ar-H), 7.51-7.54 (m,
2H, Ar-H), 7.56-7.59 (d, 1H, Ar-H), 7.99 (br s, 1H, NH), 8.77 (br s, 1H, NH), 11.49 (br s, 1H, NH); MS
SOME NOVEL THIOSEMICARBAZIDES
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Vol.4, No.4(2011), 736-743
(m/z): 401 [M+], 403 [M++2]; Anal. Calcd for C19H20N5OSCl: C, 56.78; H, 5.02; Cl, 8.82; Found: C,
56.83; H, 5.03; Cl, 8.86.
1-(4-oxo-3-butyl-3H - quinazolin-2-yl)-4-(2-aminopyridyl) thiosemicarbazide (AS8)
Yield: 80 %; mp: 145-147 ˚C; IR (KBr) cm-1: 3522 (NH), 3365 (NH), 1632 (C=O), 1223 (C=S);
1
H NMR (CDCl3): δ 1.12-1.17 (t, 3H, CH3), 1.68-1.72 (m, 2H, CH2), 2.08-2.15 (m, 2H, CH2), 3.76-3.79
(m, 2H, CH2), 7.21-7.23 (d, 1H, Ar-H), 7.30-7.39 (m, 6H, Ar-H), 7.93-7.97 (d, 1H, Ar-H), 8.12 (br s, 1H,
NH), 8.21 (br s, 1H, NH), 10.36 (br s, 1H, NH); MS (m/z): 368; Anal. Calcd for C18H20N6OS: C, 58.68;
H, 5.47; N, 22.81: Found: C, 58.66; H, 5.45; N, 22.86;
1-(4-oxo-3-butyl-3H-quinazolin-2-yl)-4-(benzyl) thiosemicarbazide (AS9)
Yield: 80 %; mp: 125-127 ˚C; IR (KBr) cm-1: 3380 (NH), 3239 (NH), 1676 (C=O), 1214 (C=S);
1
H NMR (CDCl3): δ 0.93-0.96 (t, 3H, CH3), 1.52 (s, 2H, CH2), 1.76-1.78 (m, 2H, CH2), 2.17-2.20 (m, 2H,
CH2), 3.86-3.90 (m, 2H, CH2), 7.15-7.18 (d, 1H, Ar-H), 7.37-7.46 (m, 6H, Ar-H), 7.73-7.76 (d, 1H, ArH), 8.04 (br s, 1H, NH), 8.27 (br s, 1H, NH), 10.48 (br s, 1H, NH); MS (m/z): 381; Anal. Calcd for
C20H23N5OS: C, 62.97; H, 6.08; N, 18.36: Found: C, 62.98; H, 6.06; N, 18.45.
1-(4-oxo-3-butyl-3H -quinazolin-2-yl)-4-(cyclohexyl) thiosemicarbazide (AS10)
Yield: 80 %; mp: 130-132 ˚C; IR (KBr) cm-1: 3383 (NH), 3299 (NH), 1653 (C=O), 1227 (C=S);
1
H NMR (CDCl3): δ 1.02-1.05 (t, 3H, CH3), 1.55-1.59 (m, 2H, CH2), 1.96-2.01 (m, 2H, CH2), 2.27-2.32
(m, 6H, CH2), 2.31-2.38 (m, 4H, CH2), 2.91-2.94 (m, 1H, CH), 3.81-3.85 (m, 6H, CH2), 7.31-7.42 (m,
4H, Ar-H), 8.05 (br s, 1H, NH), 8.49 (br s, 1H, NH), 10.32 (br s, 1H, NH); MS (m/z): 373; Anal. Calcd
for C19H27N5OS: C, 61.10; H, 7.29; N, 18.75: Found: C, 61.16; H, 7.35; N, 18.71.
S.typhi
63
125
63
E.Coli
63
63
63
S.flexneri
125
125
63
P.vulgaris
63
63
125
Enterobacter spp.
125
125
125
K.pneumoniae
63
63
63
S.enteritidis
125
63
63
B.subtilis
125
63
63
S.flexneri
125
125
125
P.aeruginosa
63
125
125
*Gatifloxacin used as a reference standard against
standard for other bacteria. MIC of INH = 0.4 µg/mL
6
25
25
125
63
63
32
63
125
63
63
63
32
32
63
63
63
125
63
63
63
125
125
125
125
125
63
63
63
125
63
125
125
63
63
63
125
125
125
63
32
32
63
125
63
63
63
63
32
63
63
63
125
63
63
32
63
63
63
63
125
63
63
125
125
125
63
125
63
63
125
63
125
M. tuberculosis whereas Ciprofloxacin used as a
Standard
6
AS10
6
AS9
AS5
25
AS8
13
AS7
13
AS6
13
AS4
25
AS3
M. Tuberculosis
AS2
Microorganisms
AS1
Table-1: Antibacterial activity (MIC In µg/mL) of 1-(4-oxo-3-butyl-3H-quinazolin-2-yl)-4-(substituted)
Thiosemicarbazides (AS1-AS10)
1
4
2
1
1
1
1
1
1
1
1
reference
Antitubercular activity
The synthesized compounds were screened for their in vitro antimycobacterial activity against
Mycobacterium tuberculosis strain H37Rv at the Tuberculosis Antimicrobial screening centre, Birla
Institute of Technology & Sciences, Hyderabad campus, Hyderabad. The results are expressed in terms of
Minimum Inhibitory Concentration (MIC).
The results of antimycobacterial activity depicted in Table 1, indicate that the test compounds
inhibited the growth of mycobacterium in varying degree. Compounds with electron withdrawing
SOME NOVEL THIOSEMICARBAZIDES
741
V. Alagarsamy and P. Parthiban
Vol.4, No.4(2011), 736-743
substituent on the aryl ring showed better activity over the unsubstituted or electron donating substituent
on the aryl ring. Among the test compounds, 1-(4-oxo-3-butyl-3,4dihydroquinazolin-2-yl)-4-(2nitrophenyl)thiosemi carbazides (AS6), 1-(4-oxo-3-butyl-3,4dihydroquinazolin-2-yl)-4-(4-chloro phenyl)
thiosemicarbazides
(AS7)
and
1-(4-oxo-3-butyl-3,4-dihydroquinazolin-2-yl)-4-(2pyridyl)thiosemicarbazides (AS8) exhibited the antitubercular activity a the minimum micro gram
concentration (6µg/ml).
Antibacterial activity
The title compounds are screened for their antibacterial activity against different gram positive
and gram negative bacteria by agar dilution method, the results are depicted in Table-1. Among the
different substituents on the aryl ring with electron withdrawing substituent showed better activity over
the unsubstituted and electron donating substituent. Compounds AS6 and AS7 emerged as the most active
compounds of the series. Compound AS6 shown most potent activity against E. coli and K. pneumoniae
while the compound AS7 showed most potent activity against S. typhi, E. coli, K. pneumoniae, S.
enteritidis and B. subtilis.
CONCLUSION
In summary the synthesis of new series of 1-(4-oxo-3-butyl-3H-dihydroquinazolin-2-yl)-4-(substituted)
thiosemicarbazides has been described. These derivatives have exhibited significant antibacterial activity
against the various gram positive and gram negative bacteria including M. tuberculosis. Among the series
1-(4-oxo-3-butyl-3,4-dihydroquinazolin-2-yl)-4-(2-nitrophenyl) thiosemicarbazide (AS6), 1-(4-oxo-3butyl-3,4-dihydroquinazolin-2yl)-4-(4-chlorophenyl) thiosemicarbazide (AS7) was found to be the most
active antimicrobial agents, with the MIC of 32 µg/ml. Interestingly these compounds also showed
significant antitubercular activity (Compound AS6 and AS7 showed activity at 6µg/ml), offering potential
for further optimization and development to new antitubercular agents.
ACKNOWLEDGEMENTS
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, Associate Professor, Birla Institute
of Technology & Sciences, Hyderabad campus for performing antitubercular screening of the test
compounds. The authors are also wish to thank the management of MNR College of Pharmacy for
providing infrastructure facilities to carry out this research work.
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