Studies on arylfuran derivatives. Part VII. Synthesis and characterization of some Mannich bases carrying halophenylfuryl moieties as promising antibacterial agents

Article abstract of DOI:10.1016/S0014-827X(98)00058-5

A series of 4-[5-(halophenyl)-2-furfurylidene)]amino-3-mercapto-5-substituted-1,2,4 -triazoles (3) were synthesized. Aminomethylation of 3 with formaldehyde and a secondary amine furnished Mannich bases, 4. Both Schiff bases and Mannich bases were characterized on the basis of IR, NMR, mass spectral data and elemental analysis. All the newly synthesized compounds were tested for their antibacterial activities. Some of them carrying morpholino and N-methylpiperazino residues were found to be promising antibacterial agents.

Full text of DOI:10.1016/S0014-827X(98)00058-5

Il Farmaco 53 (1998) 531±535
Studies on arylfuran derivatives
Part VII. Synthesis and characterization of some Mannich bases carrying
halophenylfuryl moieties as promising antibacterial agents
a,
a
B. Shivarama Holla , M.K. Shivananda , M. Shalini Shenoy , Georgy Antony
b
b
*
aDepartment of Chemistry, Mangalore University, Mangalagangotri 574 199, India
bDepartment of Microbiology, KMC, Mangalore 575 011, India
Received 15 January 1998; accepted 31 August 1998
Abstract
A series of 4-[5-(halophenyl)-2-furfurylidene)]amino-3-mercapto-5-substituted-1,2,4-triazoles (3) were synthesized. Aminomethylation
of 3 with formaldehyde and a secondary amine furnished Mannich bases, 4. Both Schiff bases and Mannich bases were characterized on the
basis of IR, NMR, mass spectra1 data and elemental analysis. All the newly synthesized compounds were tested for their antibacterial
activities. Some of them carrying morpholino and N-methylpiperazino residues were found to be promising antibacterial agents. q 1998
Elsevier Science S.A. All rights reserved.
Keywords: Arylfuran derivatives; Schiff bases; Mannich bases; Antibacterial activity
1. Introduction
2. Chemistry
Triazoles are reported to possess signi®cant antibacterial,
antifungal and anthelminthic activities [1±5]. Further, aryl-
furan-2-carboxaldehyde derivatives are also found to
possess antibacterial activity [6±8]. This gave a great
impetus to the search for potential pharmacologically active
drugs carrying arylfuran substituents. It is also reported that
the introduction of halogen atom augments the antimicro-
bial properties of the system [9].
In recent years, Mannich bases have gained importance
due to their application in pharmaceutical chemistry. They
have been encountered with antibacterial, antiviral, antifun-
gal,antimalarialandCNSdepressantactivities[10,11].Many
Mannich bases of 1,2,4-triazoles carrying N-methylpiper-
azine substituents possess protozoacidal and bactericidal
activities. Hence, in continuation of our work on arylfuran
derivatives [12±14] with enhanced therapeutic values and in
order to modify the structure of nitrofuran drugs [15,16], we
decided to synthesize a series of aminomethyl-3-substituted-
4-(5-aryl-2-furfurylidene) amino-1,2,4-triazole-5-thiones
(4) starting from the respective Schiff bases (3).
p-Chlorophenylfurfural and p-bromophenylfurfural were
synthesized through the Meerwein reaction [17]. 3-Alkyl-
substituted 4-amino-5-mercapto-s-triazoles (1) were pre-
pared according to Baeyer's procedure [18] by re¯uxing
thiocarbohydrazide with suitable aliphatic carboxylic
acids. 3-Aryl-4-amino-5-mercapto-s-triazole was prepared
by adopting the procedure of Reid and Heindel [19], viz.
hydrazinolysis of the corresponding potassium aroyl dithio-
carbazinates. In order to study the structure activity relation-
ships, two halo substituents (X ˆ Cl and Br) and three
secondary amines, viz. morpholine, N-methylpiperazine
and piperidine were used for the present investigation.
The triazoles (1) were condensed with p-halophenylfur-
fural (2) in the presence of a few drops of concentrated
sulfuric acid as a catalyst to produce Schiff bases (3) in
rather good yields. These Schiff bases (3) were then reacted
with secondary amines in the presence of formaldehyde in
ethanol or dimethylformamide±ethanol media to produce
Mannich bases (4) (Scheme 1). The structures of Schiff
bases (3) and Mannich bases (4) were established on the
basis of elemental analysis, IR, NMR and mass spectral
data. The characterization data of these compounds are
given in Tables 1 and 2, respectively.
* Corresponding author. Tel.: 1 91-742-262; e-mail: root@mnglr.
ernet.in
0014-827X/98/$ - see front matter q 1998 Elsevier Science S.A. All rights reserved.
PII S0014-827X(98)00058-5

532
B. Shivarama Holla et al. / Il Farmaco 53 (1998) 531±535
The reaction proceeds via the formation of immonium
salt which subsequently attacks the N-1 of triazole giving
rise to regioselective Mannich bases.
The IR spectrum of compound 3a showed an absorption
band at 1612 cm21 indicating the presence of CyN in the
ring. Thus the formation of an iminomethine functional
group in the compound was indicated. The absorption
band observed at 3096 cm21 could be attributed to an NH/
SH functional group, while the absorption band appearing at
738 cm21 was due to the 1,4-disubstituted phenyl ring.
In the PMR spectra of hydrazones 3b and 3d, a sharp,
singlet corresponding to one proton characteristic of the
±NyCH± group was observed at d 10.05. A down®eld
signal appearing at d 13.42 is attributable to the
±NyCH±SH moiety indicating the easy thione±thiol
tautomerism. The AB coupling of the protons of the para
substituted phenyl ring resulted in the formation of two
doublets at d 7.85 (J ˆ 8:0 Hz) and 7.25 (J ˆ 8:0 Hz)
respectively, while the two b protons of the furan ring reso-
nated as two doublets at d 7.11 (J ˆ 3:7 Hz) and 6.83
(J ˆ 3:7 Hz) respectively integrating for two protons. The
methyl protons of 3d appeared as a sharp singlet at d 1.32
(J ˆ 7:4 Hz) and the ethyl protons of 3b appeared as a
triplet and a quartet at d 1.32 (J ˆ 7:4 Hz) and 2.44
(J ˆ 7:4 Hz), respectively.
The mass spectra of compounds 3a and 3d were found
to be consistent with the assigned structures. Molecular
ions of these Schiff bases were observed at m/z 318/320
and 362/364, respectively, corresponding to the mole-
cular formulae C14H11ClN4OS and C14H11BrN4OS, respec-
tively. The base peaks, however, were observed at m/z
203/205 and m/z 247/249, respectively, which indicate
the formation of molecular ions of p-chlorophenyl-
furonitrile and p-bromophenylfuronitrile during the frag-
Scheme 1.
Table 1
Characterization data of 4-(5-aryl-2-furfurylidene)amino-3-mercapto-5-substituted-S-triazoles (3)a
Compound no.
X
R
M.p. (8C)
Yield (%)
Molecular formula
Anal. % N found (calc.)
3a
3b
3c
3d
3e
Cl
Cl
Cl
Br
Br
CH3
288
243
235
284
240
84
86
81
85
87
C14H11ClN4OS
C15H13ClN4OS
C20H15ClN4OS
C14H11BrN4OS
C15H13BrN4OS
17.75 (17.61)
17.12 (16.87)
14.49 (14.20)
15.69 (15.46)
15.24 (14.89)
C2H5
PhCH2
CH3
C2H5
aIR (n cm21): 3a, 3096 (NH/SH), 1612 (CyN), 738 (p-ArH); 3d, 3056 (NH/SH), 1598 (CyN), 724 (p-ArH). 1H NMR (90 MHz, DMSO-d6): 3b, d, 13.42 (s,
1H, ±NyC±SH), 10.05 (s, 1H, ±NyCH±), 7.85 (d, 2H, p-chlorophenyl, J ˆ 8:0 Hz), 7.25 (d, 2H, p-chlorophenyl, J ˆ 8:0 Hz), 7.11 (d, 1H, furan 4H, J ˆ 3:7
Hz), 6.83 (d, 1H, furan 3H, J ˆ 3:7 Hz), 2.44 (q, 2H, CH2, J ˆ 7:4 Hz), 1.32 (t, 3H, CH3, J ˆ 7:4 Hz). 3d, d, 13.42 (s, 1H, ±NyCySH), 10.05 (s, 1H, ±NyCH±),
7.65 (d, 2H, p-bromophenyl, J ˆ 8:4 Hz), 7.45 (d, 2H, p-bromophenyl, J ˆ 8:4 Hz), 7.19 (d, 1H, furan 4H, J ˆ 3:7 Hz), 6.99 (d, 1H, furan 3H, J ˆ 3:7 Hz),
1.21 (s, 3H, CH3). Mass: 3a, m/z 318/320 (M1, 57.1%); 3d, m/z 362/364 (M1, 8.8%).

B. Shivarama Holla et al. / Il Farmaco 53 (1998) 531±535
533
Table 2
Characterization data of 1-aminomethy1-3-substituted-4-(5-aryl-2-furfurylidene)amino-1,2,4-triazole-5-thiones (4)a
Compound no.
X
R
Z
Molecular formula
Yield (%)
M.p. (8C)
Anal. %N found (calc.)
4a
4b
4c
4d
4e
4f
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
Br
Br
Br
CH3
O
C19H20ClN5O2S
C20H23ClN6OS
C20H22ClN5OS
C21H22ClN5O2S
C21H25ClN6OS
C21H24ClN5OS
C25H24ClN5O2S
C26H27ClN6OS
C26H26ClN5OS
C19H20BrN5O2S
C20H23BrN6OS
C20H22BrN5OS
C20H22BrN5O2S
C21H25BrN6OS
C21H24BrN5OS
61
59
60
68
59
62
72
78
69
63
61
52
79
64
65
176±178
260±262
160±162
148±150
145±147
150±152
138±140
124±126
122±123
196±198
178±180
167±169
148±150
138±140
149±151
16.85 (16.79)
19.29 (19.53)
16.69 (16.86)
15 74 (15.80)
18.69 (18.92)
16.10 (16.32)
14.02 (14.20)
16.38 (16.60)
14.04 (14.26)
15.06 (15.18)
17.38 (17.72)
15.43 (15.25)
14.56 (14.74)
17.39 (17.21)
14.68 (14.80)
CH3
NMe
CH2
O
CH3
C2H5
C2H5
C2H5
PhCH2
PhCH2
PhCH2
CH3
NMe
CH2
O
4g
4h
4i
NMe
CH2
O
4j
4k
4l
CH3
CH3
NMe
CH2
O
4m
4n
4o
C2H5
C2H5
C2H5
NMe
CH2
a IR (n cm21): 4a, 1612 (CyN), 1278 (CyS) 724 (p-ArH); 4c, 1598 (CyN), 1278 (CyS), 724 (p-ArH); 4d, 1600 (CyN), 1278 (CyS), 738 (p-ArH); 4e, 1612
(CyN), 1278 (CyS), 724 (p-ArH); 4g, 1598 (CyN), 1278 (CyS), 724 (p-ArH). 1H NMR (270 MHz, DMSO-d6): (d ppm), 4a, 9.91 (s, 1H, ±NyCH±), 8.15 (d,
2H, J ˆ 8:2 Hz, p-chlorophenyl), 7.75 (d, 2H, J ˆ 8:2 Hz, p-chlorophenyl), 7.65 (d, 1H, J ˆ 3:5 Hz, furan 4H), 7.45 (d, 1H, furan 3H, J ˆ 3:5 Hz), 5.15 (s, 2H,
±NCH2N±), 3.68 (t, 4H, ±CH2O±, J ˆ 7:4 Hz), 2.65 (t, 4H, ±CH2±O±CH2±, J ˆ 7:4 Hz), 1.31 (s, 3H, CH3). 4b, 9.75 (s, 1H, ±NyCH±), 7.89 (d, 2H, p-
chlorophenyl, J ˆ 8:5 Hz), 7.58 (d, 2H, p-chlorophenyl, J ˆ 8:5 Hz), 7.51 (d, 1H, furan 4H, J ˆ 3:3 Hz), 7.36 (d, 1H, furan 3H, J ˆ 3:3 Hz), 5.01 (s, 2H,
±NCH2N±), 3.35 (s, 3H, ±NCH3), 2.66 (t, 4H, ±CH2±O±CH2±, J ˆ 7:4 Hz), 2.37 (t, 4H, ±CH2±N(Me)±CH2±, J ˆ 7:4 Hz), 1.34 s, 3H, CH3). 4e, 9.76 (s, 1H,
±NyCH±), 7.88 (d, 2H, p-chlorophenyl, J ˆ 8:5 Hz), 7.59 (d, 2H, p-chlorophenyl, J ˆ 8:5 Hz), 7.43 (d, 1H, furan 4H, J ˆ 3:6 Hz), 7.36 (d, 1H, furan 3H,
J ˆ 3:5 Hz), 5.02 (s, 2H, ±NCH2N±), 3.35 (s, 3H, ±NCH3), 2.74 (q, 2H, CH2, J ˆ 7:3 Hz), 2.67 (t, 4H,±CH2±N±CH2±, J ˆ 7:3 Hz), 2.51 (t, 4H, ±CH2±N (Me)±
CH2, J ˆ 5:4 Hz), 1.23 (t, 3H, CH3, J ˆ 7:4 Hz). Mass, 4e, m/z 444/446 (M1, 3%), 203/205 (p-chlorophenylfuronitrile, 28%), 113 (N-methylpiperazinomethyl
cation, 100%). 4j, m/z 461/463 (M1, 2%), 247/249 (p-bromophenylfuronitrile, 19%), 100 (morpholinomethyl cation, 100%). 4m, m/z 475/477 (M1, 3%), 460
(M1 2 CH3), 247/249 (p-bromophenylfuronitrile 13%), 100 (morpholinomethyl cation, 100%). 4o, m/z 473/475 (M1, 1%), 247/249 (p-bromophenylfuro-
nitrile, 32%), 98 (piperidinomethyl cation, 100%).
mentation of parent, molecular ions, analogous to our
earlier observations of the mass spectra of arylfuran hetero-
cycles [12].
In the IR spectrum of the Mannich base 4c, the absorption
band at 1598 cm21 corresponds to CyN of the ring, while
the absorption band appearing at 1278 cm21 could be attrib-
uted to the CyS functional group.
In the NMR spectrum of compound 4a, the ±NCH2N±
protons resonated as a singlet at d 5.15 integrating for two
protons. The signal due to the methyl protons of the tria-
zole moiety appeared at d 1.31 as a singlet. The ±CH2±O±
CH2± protons of the morpholine residue appeared as a
triplet at d 3.68 (J ˆ 7:4 Hz), while the ±CH2±N±CH2±
protons of the morpholine residue resonated as a triplet
at 2.65 (J ˆ 7:4 Hz). The aromatic proton signals of the
p-chlorophenyl group appeared as two doublets at d 8.15
(J ˆ 8:2 Hz) and 7.75 (J ˆ 8:2 Hz), respectively, integrat-
ing for four protons. The two b protons of the furan ring
appeared as two doublets at d 7.65 (J ˆ 3:5 Hz) and 7.45
(J ˆ 3:5 Hz), respectively, integrating for two protons. The
signal of the ±NyCH± proton was seen as a singlet at d
9.91. The NMR spectral data of some of Mannich bases are
given in Table 2.
The mass spectra of Mannich bases 4e, 4j, 4m and 4o
conformed with the assigned structures. The molecular ion
peaks were observed at m/z 444/446, 461/463, 475/477 and
473/475 which correspond to the molecular formulae
C21H25ClN6OS, C19H20BrN5O2S, C20H22BrN5O2S and
C21H24BrN5OS, respectively. These molecular ions under-
went fragmentations to produce ions at m/z 113, 100 and 98
as base peaks which correspond to N-methylpiperazino-
methyl, morpholinomethyl and piperidinomethyl cations,
respectively. The peaks appearing at m/z 203/205 and 247/
249 were ascribed to the formation of p-chlorophenylfuro-
nitrile and p-bromophenylfuronitrile. The mass spectral
fragmentation patterns of these Mannich bases along with
their relative abundances of daughter ions are given in
Scheme 2.

534
B. Shivarama Holla et al. / Il Farmaco 53 (1998) 531±535
off and recrystallized from a mixture of dimethylformamide
and ethanol (2:1) to yield the title compounds (3).
3.2. 1-Aminomethyl-3-substituted 4-5-[4-halophenyl)-2-
furfurylidene]amino-1,2,4-triazole-5-thiones (4)
The Schiff base (3; 10 mmol) was dissolved in ethanol or
a mixture of ethanol and dimethylformamide (2:1). Then,
formaldehyde (40%, 1.5 ml) and secondary amine (10
mmol) in ethanol were introduced to this solution. The
mixture was stirred for 1±2 h and kept overnight at room
temperature. The resulting solid separated was collected by
®ltration, washed with ethanol and recrystallized from a
mixture of dimethylformamide and ethanol (2:1) to yield
the title compounds.
4. Antibacterial activity
The newly synthesized compounds, 4, were initially
screened for their in vitro antibacterial activities against
Escherischia coli, Staphylococcus aureus, Pseudomonas
aeruginosa and Bacillus subtilis according to the disc diffu-
sion method [20]. The minimal inhibitory concentrations
(MIC values) of the above compounds were determined
by serial dilution method. Furacin was used as a standard
drug for comparison. The results of these studies are given
in Table 3.
The antibacterial screening data indicate that Mannich
base 4b carrying N-methylpiperazine and p-chlorophenyl-
furyl groups showed excellent antibacterial activity against
S. aureus, P. aeruginosa and B. subtilis. The compound 4d
carrying a morpholino moiety exhibited excellent antibac-
terial activity against P. aeruginosa and B. subtilis. The
compounds 4f and 4g also possessed good antibacterial
activities against P. aeruginosa and B. subtilis, respectively.
The antibacterial activities of the remaining compounds
Scheme 2.
3. Experimental
Melting points were determined by capillary method and
are uncorrected. The IR spectra (in KBr pellets) were
recorded on a Shimadzu FT-IR 157 spectrophotometer.
PMR spectra were recorded either on a Perkin±Elmer EM-
390 (90 MHz) or on a Bruker WH-200 (270 MHz) spectro-
meter using TMS as an internal standard. The mass spectra
were recorded on a Jeol JMS-D 300 spectrometer operating
at 70 eV. The purity of the compounds was checked by thin
layer chromatography (TLC) on silica gel plate.
Table 3
Antibacterial activity data of 1-aminomethyl-3-substituted-4-[5-aryl-2-
furfurylidene]amino-1,2,4-triazole-5-thiones (4)
Compound no.
Minimum inhibitory concentration mg/ml
E. coli
S. aureus
P. aeruginosa
B. subtilis
4a
4b
25
25
3
12.5
6
12.5
6
12.5
12.5
6
4c
4d
12.5
12.5
12.5
12.5
25
12.5
6
12.5
6
3.1. 3-Substituted 4-[5-(halophenyl)-2-furfurylidene]-
amino-5-mercapto-1,2,4-triazoles (3)
4e
6
12.5
6
12.5
12.5
6
4f
4g
12.5
6
12.5
12.5
12.5
6
To a suspension of suitably substituted halophenyl furfur-
aldehyde (2; 10 mmol) in dioxane (15 ml), an equimolecular
amount of the corresponding amino mercapto triazole (1)
was added. The suspension was heated until a clear solution
was obtained. Then, a few drops of concentrated sulphuric
acid were added as a catalyst and the solution was re¯uxed
for 3±4 h on a water bath. The precipitated solid was ®ltered
4h
25
25
12.5
6
4j
4k
12.5
12.5
12.5
12.5
6
12.5
25
6
4l
4n
12.5
12.5
12.5
12.5
6
12.5
6
6
4o
Furacin (standard)
6
6
6
12.5
12.5

B. Shivarama Holla et al. / Il Farmaco 53 (1998) 531±535
535
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aureus, P. aeruginosa and B. subtilis.
[3] K. Richardson, P.J. Whittle, Eur. Pat. Appl. EP 115 (1984) 416
(Chem. Abstr. l01 (1984) 230544p).
The compounds 4k, 4l, 4n, and 4o carrying a p-bromo-
phenyl group showed excellent antibacterial activity against
P. aeruginosa and compared with furacin. However, there is
no substantial difference of activities observed between two
series of compounds carrying p-chlorophenylfuryl and p-
bromophenylfuryl groups.
It was concluded that some of the compounds of the series
were found to be promising antibacterial agents and hence
deserve further pharmacological investigation.
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Acknowledgements
The authors are grateful to Head, R.S.I.C., C.D.R.I.,
Lucknow and Head, R.S.I.C., I.I.T. Madras for providing
microanalysis, IR, NMR and mass spectral data. The authors
are also thankful to Professor Ananthakrishna, Head,
Department of Microbiology, KMC, Mangalore for extend-
ing the facilities of the College for antibacterial screening.
M.K.S. is grateful to C.S.I.R., New Delhi for a Junior
Research Fellowship.
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