Synthesis, antibacterial, antifungal and anti-HIV activities of Schiff and Mannich bases derived from isatin derivatives and N-[4-(4'-chlorophenyl)thiazol-2-yl] thiosemicarbazide

Article abstract of DOI:10.1016/S0928-0987(99)00038-X

Isatin, its 5-chloro and 5-bromo derivatives have been reacted with N-[4-(4'-chlorophenyl)thiazol-2-yl] thiosemicarbazide to form Schiff bases and the N-Mannich bases of these compounds were synthesized by reacting them with formaldehyde and three seconda

Full text of DOI:10.1016/S0928-0987(99)00038-X

European Journal of Pharmaceutical Sciences 9 (1999) 25–31
www.elsevier.nl/locate/ejps
Synthesis, antibacterial, antifungal and anti-HIV activities of Schiff
and Mannich bases derived from isatin derivatives and
N-[4-(49-chlorophenyl)thiazol-2-yl] thiosemicarbazide
a
b
c
S.N. Pandeyaa , , D. Sriram , G. Nath , E. DeClercq
*
aDepartment Pharmaceutics, Institute of Technology, Banaras Hindu University, Varanasi-221005, India
bDepartment of Microbiology, Institute of Medical Sciences, Banaras Hindu University, Varanasi-221005, India
cRega Institute for Medical Research, Katholieke University-Leuven, Minder broedersstraat, B-3000 Leuven, Belgium
Received 14 March 1999; received in revised form 23 April 1999; accepted 17 May 1999
Abstract
Isatin, its 5-chloro and 5-bromo derivatives have been reacted with N-[4-(49-chlorophenyl)thiazol-2-yl] thiosemicarbazide to form
Schiff bases and the N-Mannich bases of these compounds were synthesized by reacting them with formaldehyde and three secondary
1
amines. Their chemical structures have been confirmed by means of IR, H-NMR data and by elemental analysis. Investigation of
antimicrobial activity of compounds was done by agar dilution method against 28 pathogenic bacteria, 8 pathogenic fungi and anti-HIV
activity against replication of HIV-1 (IIIB) in MT-4 cells. Among the compounds tested 1-[N,N-dimethylaminomethyl]-5-bromo
isatin-3-h19-[40-(p-chlorophenyl) thiazol-20-yl] thio semicarbazonej 10 showed the most favourable antimicrobial activity.
1999
Elsevier Science B.V. All rights reserved.
Keywords: Isatin; Thiazole; Thiosemicarbazone; Schiff bases; Mannich bases; Antimicrobial
1. Introduction
present work to synthesize Schiff and Mannich bases of
isatin derivatives and N-[4-(49-chlorophenyl) thiazol-2-yl]
thiosemicarbazide and screen for their antibacterial, an-
tifungal activity by agar dilution method and anti-HIV
activity against HIV-1 (III B) in MT-4 cells were accom-
plished.
Isatin (Indolin-2,3-dione) derivatives are reported to
show variety of biological activities like antibacterial
(Daisley and Shah, 1984) antifungal (Piscopo et al., 1987)
and anti-HIV (Pandeya et al., 1998) activities. Thiazoles
have been reported to possess antibacterial (Agarwal et al.,
1997), antifungal (Sup et al., 1995) and anti-HIV (Maass et
al., 1993) activities. It is also reported that isatin-b-
thiosemicarbazones have shown antimicrobial activity
(Teitz et al., 1994). Further amino derivative of pyridine
2-carboxaldehyde thiosemicarbazone have been found to
be shown antitumor activity (Liu et al., 1992). Recently
cytotoxic activities of Mannich bases of chalcones (Dim-
mock et al., 1998) have been reported. In view of the
antimicrobial property of the above pharmacophores, it
was envisaged that the combined effect of all the entities
will result in increased antimicrobial activity. Thus the
2. Experimental
2.1. Chemistry
The melting points were determined by using Thomas-
Hoover melting point apparatus and are uncorrected.
Spectroscopic data were recorded on the following instru-
ments IR, Jasco infrared spectrometer, Jeol FX 90Q FT-
NMR spectrometer (90 MHz). Microanalyses were per-
formed by the microanalytical unit Central Drug Research
Institute, India.
2.1.1. Synthesis of 2-amino-4-(49-chlorophenyl) thiazole
A mixture of 4-chloro acetophenone (0.1 mol), thiourea
(0.2 mol) and iodine (0.1 mol) was heated on a steam bath
*Corresponding author. Tel.: 191-542-312-305; fax: 191-542-316-
428.
E-mail address: snpande@banaras.ernet.in (S.N. Pandeya)
0928-0987/99/$ – see front matter
PII: S0928-0987(99)00038-X
1999 Elsevier Science B.V. All rights reserved.

26
S.N. Pandeya et al. / European Journal of Pharmaceutical Sciences 9 (1999) 25–31
for 4 h. The hydroiodide, thus separated, was filtered,
washed with ether and dried. It was dissolved in hot water,
filtered while hot and the clear solution neutralized with a
strong solution of ammonia. The solid separated was
filtered, washed with water and recrystallized from ben-
zene. Yield: 96%; m.p. 1458C; IR (KBr): 3320 cm21
(NH2), 1510, 1460, 1045 cm21 (characteristic of thiazole
nucleus); 1H-NMR (CDCl3) d (ppm): 3.35 (s, 2H, NH2,
D2O exchangeable), 6.75 (s, 1H, H-5), 7.21–7.56 (m, 4H,
Ar-H). Anal. (C9H7N2SCl) C, H, N.
afforded pale yellow crystals. Yield: 90%; m.p. 1758C; IR
(KBr): 1020 cm21 (C5S), 3100 cm21 (NH), 3250 cm21
(NH2); H-NMR (CDCl3) d (ppm): 2.5 (s, 2H, NH2, D2O
exchangeable), 6.30 (s, 1H, H-5), 6.92–7.75 (m, 4H, Ar-
H), 9.70 (s, 2H, 23NH, D2O exchangeable); Anal.
(C10H9N452C1) C, H, N.
1
2.1.3. Synthesis of isatin-3-h19-[40-(p-chlorophenyl)
thiazol-20-yl] thiosemi carbazonej (1)
Equimolar quantities (0.02 mol) of isatin and N-[4-(49-
chlorophenyl) thiazol-2-yl] thiosemicarbazide were dis-
solved in warm ethanol containing 1 ml of glacial acetic
acid. The reaction mixture was refluxed for 15 h and set
aside. The resultant solid was washed with dilute ethanol
dried and recrystallized from ethanol–chloroform mixture.
Yield 94.6%; m.p. 1258C, IR (KBr): 1620 cm21 (C5N),
2.1.2. Synthesis of N-[4-(49-chlorophenyl thiazol-2-yl]
thiosemicarbazide
To a solution of 2-amino-4-(49-chlorophenyl) thiazole
(0.01 mol) in DMF (10 ml) was added sodium hydroxide
(0.01 mol) and carbon disulphide (0.75 ml). The mixture
was stirred at 15–208C for 1 h, to the stirred mixture was
added hydrazine hydrate (0.01 mol) and stirring continued
at 608C for 1 h more. On adding water, a pale yellow solid
separated out which is recrystallized from DMF-ethanol
1
1015 cm21 (C5S); H-NMR (CDCl3) d (ppm): 6.2 (s, 1H,
H-59), 7.0–7.75 (m, 8H, Ar-H), 9.6 (s, 2H, 23-NH-D2O
exchangeable), 10.4 (s, 1H, NH of isatin, D2O exchange-
able) Anal. (C18H12ON5S2C1) C, H, N.
Scheme 1. Syntheses of the studied compounds.

S.N. Pandeya et al. / European Journal of Pharmaceutical Sciences 9 (1999) 25–31
27
2.1.4. Synthesis of 1-(morpholino methyl) isatin-3-hl9-
[40-(p-chlorophenyl) thiazol-20-yl] thiosemicarbazonej
(6)
A slurry consisting of the S-1 (0.005 mol), tetrahydro-
furan (5 ml) and 37% formalin (2 ml) was made. To this
morpholine (0.005 mol) was added dropwise, with cooling
and shaking. The reaction mixture was allowed to stand at
room temperature for 1 h with occasional shaking after
which it was warmed on a steam bath for 15 min. At the
end of the period the contents were cooled and the product
obtained was recrystallized from chloroform–petroleum
ether. Yield 90.4%; m.p. 1318C; IR (KBr): 1615 cm21
(C5N), 2850 cm21 (CH2); 1H-NMR (CDCl3) d (ppm):
2.6 (t, 4H, –CH2NCH2 –), 3.7 (t, 4H, –CH2OCH2 –) 4.45
(s, 2H, CH2), 6.3 (s, 1H, H-5), 6.9–7.8 (m, 7H, Ar-H),
9.45 (s, 2H, 23-NH-, D2O exchangeable); Anal.
(C23H21O2N6S2C1) C, H, N.
Table 1
Physical constants of the synthesized compounds
Code
R
R1
Yield
(%)
M.P.
8C
Mol. formula
Elemental analysis
calculated/found
% C
% H
% N
1
2
3
4
H
H
94.6
86.7
91.2
82.8
125
208
128
186
C18H12ON5S2C1
C18H11ON5S2C12
C18H11ON5S2ClBr
C21H19ON6S2C1
52.1
52.3
48.1
48.0
43.8
43.9
53.5
53.7
2.8
2.9
2.4
2.5
2.2
2.2
4.0
4.2
16.9
17.0
15.6
15.9
14.2
14.2
17.8
17.6
Cl
Br
H-
H
H
CH2-N(CH3)2
5
H
91.3
122
C24H23ON6S2C1
56.3
56.4
4.5
4.6
16.4
16.4
6
7
H
90.4
89.0
131
268
C23H21O2N6S2C1
C21H18ON6S2C12
53.7
53.8
49.8
49.1
4.0
4.1
3.5
3.5
16.3
16.4
16.6
16.8
Cl
-CH2-N(CH3)2
8
Cl
90.6
224
C24H22ON6S2C1
52.7
52.8
4.0
4.1
15.3
15.4
9
Cl
Br
90.4
80.0
220
197
C23H2002N6S2C12
C21H18ON6S2ClBr
50.4
50.3
45.8
45.8
3.6
3.7
3.2
3.3
15.3
15.2
15.2
15.3
10
-CH2-N(CH3)2
11
12
Br
Br
72.0
89.5
207
191
C24H22ON6S2ClBr
C23H20O2N6S2C1Br
48.8
48.5
3.7
3.7
14.2
14.2
46.6
46.6
3.3
3.4
14.2
14.0

28
S.N. Pandeya et al. / European Journal of Pharmaceutical Sciences 9 (1999) 25–31
2.2. Biological evaluation
each microorganisms were prepared to contain 105 cfu/mL
and applied to agar plates which have been serially diluted
with compounds to be tested. The plates were incubated at
268C during 48–72 h and MIC’s were determined.
2.2.1. In vitro antibacterial activity
Compounds were evaluated for their in vitro antibacter-
ial activity against 26 pathogenic bacteria procured from
Dept. of Microbiology, Institute of Medical Sciences,
Banaras Hindu University. The agar dilution method
(Barry, 1991) was performed using Mueller–Hinton agar
(Hi-Media) medium. Suspensions of each microorganisms
were prepared to contain approximately 106 colony form-
ing units (cfu)/mL and applied to plates with serially
diluted compounds to be tested and incubated at 378C for
overnight (approx. 18–20 h). The minimum inhibitory
concentration (MIC) was considered to be the lowest
concentration that completely inhibited growth on agar
plates, disregarding a single colony or a faint haze caused
by the inoculum.
2.2.3. Anti-HIV activity
The procedure to measure anti-HIV activity in MT-4
cells has been described previously (Pandeya et al., 1998).
Either mock-infected or HIV-1 infected MT-4 cells were
incubated in the presence of various concentrations of test
compounds and the number of viable cells was determined
by the MTT [3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl
tetrazolium bromide] method on day five after virus
infection.
3. Result and discussion
2.2.2. In vitro antifungal activity
In the present study N-[4-(49-Chlorophenyl)thiazol-2-yl]
thiosemicarbazide has been synthesized from 4-chloro
acetophenone. This has been condensed with isatin and its
5-chloro and 5-bromo derivatives to form Schiff bases.
The N-Mannich bases of the above Schiff bases were
synthesized by condensing acidic imino group of isatin
with formaldehyde and secondary amines (Scheme 1). All
The compounds were evaluated for their in vitro an-
tifungal activity against Cryptococus neoformans, Micros-
porum audouinii, Trichophyton mentagrophytes, Micros-
porum gypsum, Histoplasma capsulatum, Candida al-
bicans and Aspergillus niger using agar dilution method
with Saburoud’s dextrose agar (Hi-Media). Suspensions of
Table 2
Antibacterial activity of the compounds MIC’s in mg/mLa
Microorganisms/Drugs
1
2
3
4
5
6
7
1. Salmonella typhimurium
2. Vibrio parahaemolyticus
3. Salmonella paratyphi B
4. Edwardsiella tarda
5. Vibrio cholerae 0139
6. Staphylococcus aureus (G1ve)
7. Escherchia coli NCTC 10418
8. Vibrio cholerae non-01
9. Enterococcus faecalis (G1ve)
10. Salmonella typhi
11. Pseudomonas aeruginosa
12. Klebsiella pneumoniae
13. Staphylococcus albus (G1ve)
14. Salmonella enteritidis
15. Aeromonas hydrophile
16. Vibrio cholerae-01
17. Bacillus subtilis (G1ve)
18. Shigella sonnei
19. Shigella boydii
20. Plesiomonas shigelloides
21. Proteus rettgeri
22. Shigella flexnari
23. Proteus vulgaris
24. Enterobacter
25. Morgonella morgonii
26. Citrobacter ferundii
27. Proteus morgonii
625
78.1
625
625
312.5
1250
625
39.1
4.9
312.5
2500
625
625
312.5
78.1
312.5
312.5
78.1
1250
312.5
39.1
156.2
19.5
78.1
156.2
39.1
625
312.5
39.1
2.4
156.2
1250
312.5
625
156.2
39.1
78.1
156.2
78.1
156.2
78.1
39.1
156.2
156.2
156.2
78.1
39.1
156.2
39.1
312.5
39.1
156.2
156.2
78.1
1250
156.2
19.5
312.5
78.1
312.5
312.5
156.2
1250
312.5
39.1
4.9
78.1
1250
625
625
312.5
78.1
156.2
78.1
156.2
312.5
156.2
78.1
312.5
156.2
156.2
156.2
78.1
312.5
39.1
78.1
156.2
312.5
312.5
78.1
19.5
2.4
156.2
312.5
312.5
312.5
1250
312.5
39.1
9.8
9.8
2.4
156.2
1250
312.5
312.5
312.5
156.2
156.2
156.2
78.1
156.2
1250
625
312.5
156.2
156.2
78.1
156.2
156.2
156.2
156.2
156.2
78.1
156.2
156.2
78.1
156.2
1250
312.5
625
156.2
78.1
78.1
625
156.2
312.5
78.1
156.2
39.1
156.2
78.1
78.1
78.1
39.1
78.1
78.1
39.1
78.1
156.2
78.1
78.1
625
312.5
156.2
312.5
312.5
156.2
312.5
312.5
156.2
312.5
312.5
156.2
156.2
156.2
312.5
156.2
78.1
156.2
156.2
156.2
312.5
39.1
156.2
78.1
156.2
156.2
39.1
156.2
78.1
156.2
312.5
78.12
156.2
312.5
156.2
312.5
78.1
78.1
156.2
19.5
312.5
156.2
312.5
156.2
28. Salmonella paratyphi B
a MIC – Minimum inhibitory concentration.

S.N. Pandeya et al. / European Journal of Pharmaceutical Sciences 9 (1999) 25–31
29
Table 3
Antibacterial activity of the compounds MIC’s in mg/mLa
Microorganisms/Drugs
8
9
10
78.1
11
12
156.2
39.1
156.2
156.2
156.2
625
156.2
39.1
4.9
156.2
1250
625
156.2
156.2
78.1
Suiphamethoxazole
Trimethoprim
1. Salmonella typhimurium
2. Vibrio parahaemolyticus
3. Salmonella paratyphi B
4. Edwardsiella tarda
5. Vibrio cholerae 0139
6. Staphylococcus aureus (G1ve)
7. Escherchia coli NCTC 10418
8. Vibrio cholerae non-01
9. Enterococcus faecalis (G1ve)
10. Salmonella typhi
11. Pseudomonas aeruginosa
12. Klebsiella pneumoniae
13. Staphylococcus albus (G1ve)
14. Salmonella enteritidis
15. Aeromonas hydrophile
16. Vibrio cholerae-01
17. Bacillus subtilis (G1ve)
18. Shigella sonnei
19. Shigella boydii
20. Plesiomonas shigelloides
21. Proteus rettgeri
22. Shigella flexnari
23. Proteus vulgaris
24. Enterobacter
25. Morgonella morgonii
26. Citrobacter ferundii
27. Proteus morgonii
312.5
78.1
312.5
156.2
78.1
625
156.2
39.1
312.5
156.2
156.2
156.2
156.2
625
156.2
78.1
156.2
312.5
39.1
625
312.5
39.1
4.9
5000
1250
5000
5000
.5000
5000
2500
312.5
5000
2500
78.12
2500
2500
2500
2500
5000
5000
2500
2500
5000
2500
2500
2500
1250
2500
5000
5000
2500
5000
2.4
39.1
39.1
78.1
78.1
312.5
312.5
9.8
1.2
156.2
625
9.8
312.5
39.1
.5000
19.5
1.2
78.1
4.9
5000
5000
.5000
4.9
312.5
39.1
9.8
9.8
156.2
625
156.2
156.2
156.2
78.1
39.1
156.2
39.1
156.2
625
78.1
625
312.5
156.2
312.5
156.2
78.1
625
312.5
156.2
156.2
78.1
78.1
156.2
78.1
156.2
156.2
78.1
39.1
78.1
39.1
78.1
78.1
78.1
78.1
78.1
78.1
78.1
39.1
78.1
19.5
78.1
156.2
156.2
9.8
39.1
39.1
19.5
39.1
78.1
19.5
1250
5000
5000
9.8
156.2
78.1
78.1
78.1
156.2
156.2
156.2
156.2
78.1
39.1
156.2
19.5
78.1
39.1
39.1
156.2
156.2
39.1
312.5
156.2
78.1
156.2
78.1
156.2
156.2
9.8
4.9
2500
156.2
156.2
156.2
156.2
19.5
156.2
156.2
156.2
78.1
156.2
312.5
78.1
78.1
78.1
39.1
156.2
78.1
28. Salmonella paratyphi B
a MIC – Minimum inhibitory concentration.
compounds (Table 1) gave satisfactory elemental analysis.
IR and H-NMR spectra were consistent with the assigned
bases. The site of action of thiosemicarbazones is the
enzyme ribonucleotide reductase (RR) (Liu et al., 1992).
Deoxyribonucleotides the blocks of DNA, which are
derived from corresponding ribonucleotide, by reaction in
which the 2-carbon atom of the D-ribose portion of the
ribonucleotide is directly reduced to form the 2-deoxy
derivative. The substrate for this reaction is catalysed by
RR. Antimicrobial activity of thiosemicarbazones synthes-
ized in the present study could be based on the inactivation
of RR. Inactivation of RR in general leads to the reduction
of intracelluar pools of deoxynucleotides and this will
affect the biosynthesis of DNA. Further it has been
observed that Mannich bases derived from a,b-unsaturated
ketones inhibit DNA and protein synthesis marketly (Dim-
mock and Kumar, 1997) and such compounds do not
inhibit dihydrofolate reductase. Thus taking into the ac-
count of the both Mannich bases and thiosemicarbazones,
the possible mechanism of present compounds could be
inhibition of DNA synthesis by controlling the inhibition
of RR.
1
structures. All the synthesized compounds were tested for
in vitro antibacterial activity by agar dilution method. The
MIC’s of the compounds against 28 pathogenic bacteria
are presented in Tables 2 and 3. Also included is the
activity of reference compounds sulphamethoxazole and
trimethoprim. It has been observed that all the compounds
tested showed mild to moderate activity against tested
bacteria. All the compounds showed more activity (less
MIC) than sulphamethoxazole except Pseudomonas
aeruginosa. When compared to trimethoprim all the com-
pounds are more active against Salmonella typhimurium,
Staphylococcus aureus, Enterococcus faecalis, Salmonella
typhi, Pseudomonas aeruginosa, Klebsiella pneumoniae,
Staphylococcus albus, Aeromonas hydrophile, Vibrio
cholerae-01, Bacillus subtilis, Proteus rettgeri, seven
compounds are more active against Edwardsiella tarda,
Proteus vulgaris and Salmonella paratyphi A, four com-
pounds are more active against Shigella flexnari, En-
terobacter and Proteus morgonii and six compounds are
more active against Morgonella morgonii. In general the
antibacterial activity of the substituents at the 5th position
is Br.Cl.H. In case of substitution at the 1st position in
Mannich bases the dimethylaminomethyl derivative
showed better activity as compared to other Mannich
The antifungal activity of the compounds was studied
with eight pathogenic fungi. The results are summarized in
Table 4. Clotrimazole has been used as reference for
inhibitory activity against fungi. All the compounds
showed good antifungal activity. When compared to clot-
rimazole, 10 compounds are more active (MIC: 1.2 mg/

30
S.N. Pandeya et al. / European Journal of Pharmaceutical Sciences 9 (1999) 25–31
Table 4
Antifungal activity of the compounds MIC’s in mg/mL
Drugs/
Microorganism
Cryptococcus
neoformans
Microsporum Trichophyton
Epidermophyton Microsporum Histoplasma Candida
Aspergillus
niger
audouinii
mentagrophytes floccosum
gypsum
capsulatum
albicans
1
2
3
4
5
6
7
8
9
10
11
12
4.9
2.4
4.9
4.9
4.9
2.4
2.4
4.9
4.9
2.4
4.9
9.8
2.4
4.9
2.4
2.4
4.9
2.4
1.2
2.4
4.9
2.4
2.4
9.8
4.9
4.9
9.8
4.9
1.2
4.9
4.9
2.4
2.4
4.9
2.4
2.4
2.4
9.8
2.4
1.2
1.2
2.4
1.2
2.4
2.4
1.2
4.9
2.4
2.4
1.2
1.2
2.4
2.4
1.2
1.2
1.2
1.2
1.2
1.2
1.2
2.4
1.2
1.2
1.2
2.4
39.l
156.2
78.1
39.1
78.1
156.5
156.5
78.2
78.1
78.1
78.1
78.1
78.1
0.3
39.1
19.5
9.8
39.1
39.1
9.8
19.5
9.8
9.8
9.8
9.8
9.8
2.4
19.5
19.5
78.1
39.1
39.1
19.5
19.5
19.5
19.5
39.1
78.1
19.5
Clotrimazole
mL) and two compounds are equipotent (2.4 mg/mL)
against Microsporum gypsum, seven compounds are more
active (MIC: ,4.8 mg/mL against Microsporum au-
douinii, six compounds are more active (MIC: 1.2 mg/mL)
against Epidermophyton floccosum. All the compounds
inhibit Cryptococcus neoformans, Microsporum audouinii,
Trichophyton mentagrophytes, Epidermophyton floccosum
and Microsporum gypsum with MIC of less than 10
mg/mL.
Compound 1-[N,N-dimethyl amino methyl]-5-bromo
isatin 3-h19-[40-(p-chlorophenyl) thiazol-20-yl] thiosemi-
carbazonej 10 showed the most favourable antimicrobial
activity.
hydrophobic group is necessary (Teitz et al., 1994) where-
as in our case, we have a big p-chlorophenyl thiazolyl
group at thiosemicarbazide end.
Acknowledgements
The authors would like to express their gratitude and
thanks to the Head, Dept. of Pharmaceutics and Dept. of
Microbiology, Banaras Hindu University for providing
necessary facilities for this research work.
The synthesized compounds were evaluated for their
inhibitory effect of the replication of HIV-1 in human
MT-4 cells. None of the compounds showed marked anti-
HIV at a concentration significantly below their toxicity
threshold (Table 5). This may be due to the fact that these
drugs may not be inhibiting the HIV-1 reverse transcriptase
(RT). It appears that for this RT inhibitory effect a small
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Table 5
Anti-HIV activity of the compounds
Compounds
EC50a, mg/mL
CC50b, mg/mL
SIc
1
2
3
4
5
6
7
8
9
.12
.10
.10
.54
.57
.19
.10
.12
.12
.29
.21
.14
12.1
10.1
10.4
53.8
57.2
19.4
10.3
11.8
11.7
29.2
20.7
13.7
,1
,1
,1
,1
,1
,1
,1
,1
,1
,1
,1
,1
10
11
12
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