Journal of the Iranian Chemical Society

https://doi.org/10.1007/s13738-021-02228-6

ORIGINAL PAPER

Synthetic and biological studies on some new camphor

thiazolidinones
Ahmed M. Abo‑Bakr1   · Entesar A. Hassan1 · Al‑Hassan S. Mahdy1 · Salem E. Zayed1

Received: 27 December 2020 / Accepted: 26 February 2021

© Iranian Chemical Society 2021

Abstract 
Camphor thiosemicarbazone 1 was utilized in the synthesis of new thiazolidinones. Thus, the reaction of 1 with ethyl
bromoacetate, dimethyl acetylenedicarboxylate and maleic anhydride afforded the corresponding thiazolidinone 2, thiazo-
lidinylidene acetate 3 and thiazolidinyl acetic acid 4, respectively. The acid 4 underwent esterification to afford the ester
5. Treatment of compounds 2, 3 and 5 with appropriate reagents afforded the newly camphor thiazolidinone derivatives
6a,b–14a,b. The elemental analysis, FT-IR, 1H NMR, 13C NMR and mass spectra confirm the chemical structure of the new
thiazolidinones. The potential use of some selected derivatives as antibacterial and antifungal agents was investigated and
gave promising results.
Graphic Abstract

Keywords  Camphor · Thiazolidinones · Camphor thiosemicarbazone · Antibacterial agents

Extended author information available on the last page of the article

13
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Introduction
Camphor is a wonderful natural compound that has a clear
biological effect, as it was used in ancient times for treat-
ment of heart disease, where it was taken orally in small
doses (50 mg), also it has been used for treatment of circula-
tory disorders [1]. Several studies in the field of medicinal
chemistry have proven that camphor derivatives possess a
range of beneficial biological activities, being an antimi-
crobial [2, 3], antiviral [4–8], antitubercular, anticancer [9,
10, topically applied analgesic [11] and treatment of type 2
diabetes mellitus [12] have cardiovascular effects [13] and
penetration enhancer for the transdermal delivery of drugs
with differing lipophilicity [14]. In addition to other uses
such as manufacturing of fumigants, perfumes, food flavor-
ings, household cleaners and cosmetics [15]. On the other
hand, the presence of activated five-membered rings con-
taining nitrogen such as thiazolidine ring which is likely
to be useful in the study of the composition of new drugs
attracted attention greatly because it is considered the basic
moiety of various pharmaceutical products. So, the thiazo-
lidinone derivatives have a wide range of pharmacological
effects including antibacterial [16], antifungal [17, 18], anti-
viral [19], anti-inflammatory [20], analgesic [21], anticancer
[22–24] and antioxidant activities [25, 26]. Many medicines
containing a thiazolidinone moiety are available commer-
cially as shown in Fig. 1.
In view of these facts, the present study led to a straight-
forward evolution for the synthesis of new thiazolidinone
derivatives connected with camphor and functionalized with
carboxymethyl, imino, cyanomethyl, ylidine acetate aceta-
mido and acetohydrazide groups and evolution of these
derivatives as potential antibacterial and antimycol agents.
Fig. 1  Examples of some drugs S
containing thiazolidinone ring
N O
S S
O S
O N
LJ-001
(antiviral agent)
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Journal of the Iranian Chemical Society
Experimental
Melting points (uncorrected) were recorded on an electro-
thermal melting apparatus (OMEL-TEMP II, USA). Reac-
tions were monitored by thin-layer chromatography (TLC).
The FT-IR spectra were recorded on a Shimadzu FT-IR 8101
PC spectrometer and carried out at the “Central Lab.” of
South Valley University. The 1H NMR and 13C NMR spec-
tra were carried out at Sohag and Mansoura University and
determined on Bruker (400 MHz) spectrometer and JEOL-
ECA500II (500 MHz); chemical shifts are reported in ppm
with TMS as an internal standard and are given in δ units.
Electron impact mass spectra were obtained at 70 eV using
a Shimadzu Qp-2010 Plus spectrometer. Elemental analysis
and mass spectra were carried out at the “Micro Analytical
Center” of Cairo University. The antimicrobial evaluation
was carried out at the Faculty of Pharmacy, Mansoura Uni-
versity. Additional data are given in Online Resource.
Camphor thiosemicarbazone (1) was prepared accord-
ing to Brousse BN et al. [27] via reaction of camphor with
thiosemicarbazide in hot ethanol with few drops of sulfu-
ric acid. Furthermore, Ousidi A. et al. [28] described the
synthesis of 2-((1,7,7-trimethylbicyclo[2.2.1]heptan-
2-ylidene)hydrazono)thiazolidin-4-one (2) via reaction of
camphor thiosemicarbazone 1 with ethylbromoacetate as a
cyclization agent in ethanol.
Methyl‑2‑((4‑oxo‑2‑(1,7,7‑trimethylbicyclo[2.2.1]
heptan‑2‑ylidene)hydrazono)thiazolidin‑5‑ylidene)
acetate (3)
To a solution of compound 1 (2.25 g, 0.01 mol) in methanol
(20 ml), dimethyl acetylene dicarboxylate (1.42 g, 0.01 mol)
was added dropwise with stirring at room temperature, after
O
N O O
OH
HN
O
piprozolin Actithiazic acid
(anti-inflammatory agent) (antibiotic agent)
tub-t O
HO
S
tub-t NH2
Darbufelone
(anti-inflammatory agent)
Journal of the Iranian Chemical Society
15 min, yellow precipitate is formed. The reaction mixture
was stirred at room temperature until TLC (chloroform/
methanol, 5:1) indicated complete consumption of the com-
pound 1, then the formed solid collected by filtration and
recrystallized from methanol as yellow crystals.
Yield 3.05 g (91%), yellow crystals, mp 212–214 °C. IR
(KBr) v /cm−1: 2955 (­ CHalkyl), 1698 and 1661 (C = O), 1578
(C = N). 1H NMR (400 MHz), ­CDCl3, δ (ppm): 0.84 (3H,
s, ­CH3), 0.98 (3H, s, ­CH3), 1.10 (3H, s, ­CH3), 1.27–1.90
(4H, m, ­CH2–CH2), 2.20 (1H, m, CH), 2.64–268 (2H, m,
N = C–CH2), 3.88 (3H, s, ­OCH3), 6.89 (1H, s,  =  CH), 11.55
(1H, s, NH, ­D2O exchangeable). 13C NMR (100  MHz),
­C DCl 3, δ (ppm); 11.05 (­CH 3), 18.71 and 19.57 (gem.
­2CH3), 27.08 and 32.64 (­ CH2-CH2), 36.10 (­ CH2–C = N),
43.91 (–CH–), 48.08 (–C–CH3), 52.55 (–C–(CH3)2), 53.58
(–OCH3), 116.37 and 142.18 (C = C), 158.43 (–S–C = N),
165.53 (C = N), 166.38 (–O–C = O), 182.65 (HN–C = O).
Mass spectrum (EI, 70 eV), m/z (Irel, %): 335 ­[M]+ (37), 320
(11), 227 (100), 187 (28), 106 (44), 85 (38). Found, %: C
57.63; H 6.52; N 12.24; S 9.30. ­C16 ­H21N3O3S. Calculated,
%: C 57.29; H 6.31; N 12.53; S 9.56.
2‑(4‑oxo‑2‑((1,7,7‑trimethylbicyclo[2.2.1]hep‑
tan‑2‑ylidene)hydrazono)thiazolidin‑5‑yl)acetic acid
(4)
A mixture of compound 1 (2.25 g, 0.01 mol) and maleic
anhydride (0.98 g, 0.01 mol) in 20 ml benzene was heated
under reflux for 1 h, during heating white precipitate is
formed, after cooling, the precipitate filtered off, dried and
recrystallized from ethanol–benzene (1:1) as white crys-
tals. Yield 2.87 g (86%), white crystals, mp 263–265 °C. IR
(KBr) v/cm−1: 2957 ­(CHalkyl), 1729 (C = O), 1599 (C = N).
1
H NMR (400 MHz), DMSO-d6, δ (ppm): 0.73 (3H, s, C ­ H3),
0.92 (3H, s, C­ H3), 0.96 (3H, s, C
­ H3), 1.15–1.89 (4H, m,
­CH2-CH2), 2.02 (1H, m, CH), 2.42 (2H, m, N = C–CH2),
2.85–2.96 (2H, d.d, J = 7.6, 4.8 Hz, ­CH2CO,), 4.21 (1H, t,
J = 5.8 Hz, SCH,), 9.72 (1H, s, NH, D­ 2O exchangeable), 13.1
(1H, s, COOH, ­D2O exchangeable). 13C NMR (100 MHz),
DMSO-d6, δ(ppm): 11.28 ­(CH3), 18.56 and 19.30 (gem.
­2CH3), 26.80 and 32.33 (­ CH2-CH2), 35.85 (­ CH2–C = N),
36.85 ­(CH2CO), 43.04 (-CH-), 43.26 (-S-CH), 47.46 (-C-
CH3), 52.26 (–C–(CH3)2), 160.71 (–S–C  =  N), 171.84
(C = N), 175.34 (–O–C = O), 177.40 (HN–C = O). Mass
spectrum (EI, 70 eV), m/z (Irel, %): 323 ­[M]+ (36), 308 (11),
280 (5), 215 (100), 149 (34), 55 (89). Found, %: C 55.93;
H 6.27; N 22.08; S 9.88. ­C15H21N3O3S. Calculated, %: C
55.71; H 6.55; N 21.99; S 9.91.
Ethyl‑2‑(4‑oxo‑2‑((1,7,7‑trimethylbicyclo[2.2.1]hep‑
tan‑2‑ylidene)hydrazono)thiazolidin‑5‑yl)acetate (5)
A mixture of compound 4 (3.23 g, 0.01 mol) and 10 ml
ethanol with few drops of concentrated sulfuric acid was
refluxed for 2 h. Then the mixture was concentrated under
reduced pressure to give colorless crystals. Yield 2.53 g
(72%), colorless crystals, mp 75–77 °C. IR (KBr) v/cm−1:
2959 ­(CHalkyl), 1725 (C  =  O), 1621 (C  =  N); 1H NMR
(400 MHz), DMSO-d6, δ (ppm): 0.72 (3H, s, ­CH3), 0.73
(3H, s, C­ H3), 0.91 (3H, s, C­ H3), 1.17 (3H, t, J = 7.2 Hz,
­CH3), 1.18–1.87 (4H, m, C ­ H2-CH2), 1.90 (1H, m, CH),
2.50 (2H, m, N  =  C–CH2), 2.87–3.01 (2H, d.d, J = 7.4,
4.6 Hz, ­CH2CO), 4.09 (2H, q, J = 7.2 Hz, ­OCH2), 4.21 (1H,
t, J = 5.3 Hz, SCH), 11.75 (1H,s,NH, ­D2O exchangeable).
13
C NMR (100 MHz), DMSO-d6, δ(ppm); 11.24 (­ CH3),
14.01 ­(CH3), 18.54 and 19.29 (gem. ­2CH3), 26.80 and
32.86 ­(CH2-CH2), 35.84 ­(CH2–C = N), 36.56 ­(CH2CO),
42.82 (–CH–), 43.27 (–S–CH), 47.44 (–C–CH3), 52.25
(–C–(CH3)2), 60.58 (-OCH2), 157.53 (–S–C = N), 170.08
(C = N), 175.20 (–O–C = O), 177.43 (HN–C = O). Mass
spectrum (EI, 70 eV), m/z (Irel, %): 351 ­[M]+ (68), 336 (13),
278 (28), 243 (58), 134 (37), 55 (100). Found, %: C 58.39;
H 7.43; N 11.71; S 8.82. C ­ 17H25N3O3S. Calculated, %: C,
58.1; H 7.17; N 11.96; S 9.12.
5‑(2‑oxoindolin‑3‑ylidene)‑2‑((1,7,7‑trimethylbi‑
cyclo[2.2.1]heptan‑2‑ylidene)hydrazono)thiazoli‑
din‑4‑one (6a)
To a solution of compound 2 (2.65 g, 0.01 mol) in 20 ml
glacial acetic acid, isatin (1.47 g, 0.01 mol) and sodium
acetate (1.23 g, 0.015 mol) were added. The solution was
refluxed till completion of the reaction monitored by TLC
(chloroform/methanol, 5:1). After cooling, the solid formed
was filtered, washed with water several times and recrystal-
lized from ethanol as yellowish red powder. Yield 2.84 g
(72%), yellowish red powder, mp 314–316 °C. IR (KBr)
v/cm−1: 3075 ­(CHarom), 2954 ­(CHalkyl), 1703 and 1675
(C = O), 1615 (C = N). 1H NMR (400 MHz), DMSO-d6,
δ (ppm): 0.76 (3H, s, ­CH3), 0.94 (3H, s, ­CH3), 1.04 (3H,
s, ­CH3), 1.25–1.94 (4H, m, ­CH2-CH2), 2.1 (1H, m, CH),
2.50 (2H, m, N = C–CH2), 6.92–8.84 (4H, m, aromatic-H),
11.06 (1H, s, NH(isatin), D ­ 2O exchangeable), 12.55 (1H,
s, NH(thiazolidinone), ­D2O exchangeable). Mass spectrum
(EI, 70 eV), m/z (Irel, %): 394 ­[M]+ (92), 379 (21), 351 (30),
286 (30), 175 (100), 120 (50). Found, %: C 63.39; H 5.87;
N 14.39; S 8.24. C­ 21 ­H22N4O2S. Calculated, %: C 63.94; H
5.62; N 14.20; S 8.13.
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5‑(1‑methyl‑2‑oxoindolin‑3‑ylidene)‑2‑((1,7,7‑tri‑
methylbicyclo[2.2.1]heptan‑2‑ylidene)hydrazono)
thiazolidin‑4‑one (6b)
Compound 6b was prepared by a procedure analogous to
compound 6a. Yield 3.23 g (74%), yellowish red crystals,
mp 305–307 °C. IR (KBr) v/cm−1: 3083 ­(CHarom), 2955
­(CHalkyl), 1701 and 1659 (C = O), 1608 (C = N). 1H NMR
(400 MHz), DMSO-d6, δ (ppm): 0.76 (3H, s, C ­ H3), 0.94 (3H,
s, ­CH3), 1.04 (3H, s, C
­ H3), 1.25–1.92 (4H, m, C
­ H2–CH2),
1.93 (3H, s, ­COCH 3) 2.11 (1H, m, CH), 2.50 (2H, m,
N = C−CH2), 6.90–8.88 (4H, m, aromatic), 10.92 (1H, s,
NH, ­D2O exchangeable). 13C NMR (100 MHz), DMSO-d6,
δ(ppm); 11.33 ­(CH3), 18.53 and 19.33 (gem. 2­ CH3), 21.06
­(CH3CO), 26.73 and 32.37 ­(CH2–CH2), 35.96 ­(CH2–C = N),
43.24 (–CH–), 47.61 (–C–CH 3), 52.62 (–C–(CH 3) 2),
120.39 and 142.89 (–S–C = C), 110.06, 121.67, 123.99,
127.86, 131.24, 134.05 (Ar–C), 158.34 (-S-C  =  N), 167.35
(C = N), 168.70 (–N–C = O), 172.03 ­(CH3C = O), 179.93
(HN–C = O). Mass spectrum (EI, 70 eV), m/z (Irel, %): 436
­[M]+ (6), 421 (1),394 (78), 286 (26), 175 (96), 55 (100).
Found, %: C 63.53; H 5.16; N 12.64; S 7.66. ­C23 ­H24N4O3S.
Calculated, %: C 63.28; H 5.54; N 12.83; S 7.34.
4‑oxo‑2‑((1,7,7‑trimethylbicyclo[2.2.1]hep‑
tan‑2‑ylidene)hydrazono)thiazolidine‑5‑carbalde‑
hyde (7)
To a solution of compound 2 (2.65 g, 0.01 mol) in DMF
(10 ml), phosphorus oxychloride (1.53 g, 0.01 mol) was
added dropwise in ice bath, then the mixture was stirred
for 5 h. The reaction mixture was poured on ice-water with
stirring for 1 h. The solid formed was filtered, washed with
water several times, dried and recrystallized from etha-
nol as yellow powder. Yield 2.43 g (78%), yellow pow-
der, mp 218–220  °C. IR (KBr) v/cm −1: 2956 ­(CHalkyl),
2790 ­(CHaldehyde), 1722 (C = O), 1620 (C = N). 1H NMR
(400 MHz), DMSO-d6, δ (ppm): 0.72 (3H, s, C ­ H3), 0.92 (3H,
s, ­CH3), 0.98 (3H, s, C
­ H3), 1.25–1.90 (4H, m, C ­ H2–CH2),
2.12 (1H, m, CH), 2.50 (2H, m, N = C–CH2), 9.71 (1H, s,
CHO), 11.94 (1H, s, NH, D ­ 2O exchangeable). Mass spec-
trum (EI, 70 eV), m/z (Irel, %): 311 [­ M]+ (12), 296 (3), 249
(2), 189 (12), 109 (100), 55 (66). Found, %: C 53.56; H 5.38;
Cl 11.78; N 13.76; S 10.40. ­C14H18Cl ­N3OS. Calculated, %:
C 53.93; H 5.82; Cl 11.37; N 13.48; S 10.28.
3‑(4‑oxo‑2‑((1,7,7‑trimethylbicyclo[2.2.1]hep‑
tan‑2‑ylidene)hydrazono)thiazolidin‑3‑yl) pro‑
panenitrile (8)
A mixture of compound 2 (2.65 g, 0.01 mol) and acryloni-
trile (0.53 g, 0.01 mol) in 20 ml ethanol in presence of few
drops of triethylamine was refluxed until TLC (chloroform/
13
Journal of the Iranian Chemical Society
methanol, 5:1) indicated complete consumption of com-
pound 2 (8 h). The reaction mixture was allowed to stand
at room temperature overnight. The crystals formed were
collected by filteration and dried without further purifica-
tion. Yield 2.42 g (76%), yellow crystals, mp110–112 °C. IR
(KBr) v/cm−1: 2964 (­ CHalkyl), 2250 (cyanide group), 1734
(C = O), 1592 (C = N). 1H NMR (400 MHz), DMSO-d6,
δ (ppm): 0.74 (3H, s, ­CH3), 0.93 (3H, s, ­CH3), 0.98 (3H, s,
­CH3), 1.22–1.91 (4H, m, C ­ H2–CH2), 2.10 (1H, m, CH), 2.57
(2H, m, N = C–CH2), 2.92–2.95 (2H, t, J = 9.0 Hz, ­CH2CN),
3.90 (2H, s, S ­ CH2), 3.92 (2H, t, J = 7.4 Hz, N–CH2). Mass
spectrum (EI, 70 eV), m/z (Irel, %): 318 ­[M]+ (73), 303 (10),
275 (27), 210 (21), 149 (65), 55 (100). Found, %: C 60.72;
H 6.68; N 17.35; S 10.22. C ­ 16H22N4OS. Calculated, %: C
60.35; H 6.96; N 17.59; S 10.07.
Methyl‑2‑(3‑(cyanomethyl)‑4‑oxo‑2‑((1,7,7‑tri‑
methylbicyclo[2.2.1]heptan‑2‑ylidene)hydrazono)
thiazolidin‑5‑ ylidene)acetate (9)
A mixture of compound 3 (3.21 g, 0.01 mol) and chloroace-
tonitrile (0.755 g, 0.01 mol) in 30 ml ethanol in presence of
few drops of triethylamine was refluxed until TLC (chloro-
form/methanol, 5:1) indicated complete consumption of the
compound 3 (20 h). The reaction mixture was allowed to
stand overnight at room temperature. The solid formed was
filtered, dried and recrystallized from methanol as green-
ish yellow crystals. Yield 2.73 g (73%), greenish yellow
crystals, mp 158–160 °C. IR (KBr) v/cm−1: 2957 ­(CHalkyl),
2250 (cyanide group), 1725 (C = O), 1605 (C = N). 1H NMR
(400 MHz), ­CDCl3, δ (ppm): 0.78 (3H, s, C ­ H3), 0.95 (3H, s,
­CH3), 1.10 (3H, s, ­CH3), 1.24–1.91 (4H, m, ­CH2–CH2), 2.15
(1H, m, CH), 2.60 (2H, m, N = C–CH2), 3.85 (3H, s, O ­ CH3),
4.75 (2H, S, ­CH2CN), 6.87 (1H, s, = CH). Mass spectrum
(EI, 70 eV), m/z (Irel, %): 374 ­[M]+ (69), 359 (22), 266 (20),
226 (22), 134 (48), 55 (100). Found, %: C 57.47; H 6.03;
N 14.72; S 8.96. C
­ 18H22N4O3S. Calculated, %: C 57.754; H
5.92; N 14.96; S 8.56.
Methyl‑2‑(3‑(2‑cyanoethyl)‑4‑oxo‑2‑((1,7,7‑tri‑
methylbicyclo[2.2.1]heptan‑2‑ylidene)hydrazono)
thiazolidin‑5‑ ylidene)acetate (10)
A solution of compound 3 (3.21 g, 0.01 mol) and acryloni-
trile (0.53 g, 0.01 mol) in 20 ml ethanol, in presence of few
drops of triethylamine, was refluxed until TLC (chloroform/
methanol, 5:1) indicated complete consumption of the com-
pound 3 (9 h). The reaction mixture was allowed to stand
overnight at room temperature. The solid formed was fil-
tered, dried and recrystallized from methanol as yellow crys-
tals. Yield 3.22 g (83%), yellow crystals, mp 150–152 °C.
IR (KBr) v/cm−1: 2957 ­(CHalkyl), 2251 (cyanide group),
1724 (C = O), 1603 (C = N). 1H NMR (400 MHz), ­CDCl3,
Journal of the Iranian Chemical Society
δ (ppm): 0.83 (3H, s, ­CH3), 0.98 (3H, s, ­CH3), 1.10 (3H,
s, ­CH3), 1.20–1.98 (4H, m, ­CH2-CH2), 2.16 (1H, m, CH),
2.60 (2H, m, N = C–CH2), 2.86–2.89 (2H, t, J = 8.3 Hz,
­CH2CN), 3.88 (3H, s, O ­ CH3), 4.21 (2H, t, J = 7.2  Hz,
N-CH2), 6.91 (1H, s, = CH). 13C NMR (100 MHz), ­CDCl3, δ
(ppm); 11.02 ­(CH3), 15.93 ­(CH2CN), 18.71 and 19.60 (gem.
­2CH3), 27.19 and 32.57 (­ CH2-CH2), 36.20 (­ CH2–C = N),
38.33 (–N–CH2), 43.76 (–CH–), 48.13 (–C–CH3), 52.52
(–C–(CH3)2), 53.32 (–OCH3), 116.63 (CN), 116.78 and
141.50 (C  =  C), 154.70 (–S–C  =  N), 164.47 (C = N),
166.32 (–O–C = O), 183.72 (HN–C = O). Mass spectrum
(EI, 70 eV), m/z (Irel, %): 388 ­[M]+ (54), 373 (7), 280 (19),
187 (12), 85 (57), 55 (100). Found, %: C 58.38; H 6.56; N
14.16; S 8.54. for ­C19H24N4O3S. Calculated, %: C 58.74; H
6.23; N 14.42; S 8.25.
Ethyl‑2‑(5‑(2‑methoxy‑2‑oxoethylidene)‑4‑oxo‑2
‑((1,7,7‑trimethylbicyclo[2.2.1]heptan‑2‑ylidene)
hydrazono) thiazolidin‑3‑yl)acetate (11)
A mixture of compound 3 (3.21 g, 0.01 mol) and ethyl-
chloroacetate (1.22 g, 0.01 mol) in 20 ml ethanolic sodium
ethoxide (0.68 g, 0.01 mol) was refluxed until TLC (chlo-
roform/methanol, 5:1) indicated complete consumption of
the compound 3 (10 h). The reaction mixture was filtered
on hot. The filtrate was allowed to stand overnight, and
then the solid precipitate was filtered off, dried and recrys-
tallized from methanol as yellowish green crystals. Yield
3.16 g (75%), yellowish green crystals, mp125-127 °C. IR
(KBr) v/cm−1: 2960 ­(CHalkyl), 1725, 1700 and 1670 (C = O),
1599 (C = N). 1H NMR (400 MHz), DMSO-d6, δ (ppm):
0.72 (3H, s, C ­ H3), 0.94 (3H, s, C­ H3), 1.01 (3H, s, C
­ H3),
1.19 (3H, t, J = 6.9 Hz, ­CH3), 1.20–1.90 (4H, m, C­ H2-CH2),
2.0 (1H, m, CH), 2.50 (2H, m, N = C–CH2), 3.81 (3H, s,
­OCH3), 4.17 (2H, q, J = 5.8 Hz, ­OCH2), 4.60 (2H, s, N-CH2),
6.81 (1H, s, = CH). 13C NMR (100  MHz), DMSO-d6, δ
(ppm); 11.04 (­ CH3), 14.02 (­ CH3), 18.47 and 19.23 (gem.
­2CH3), 26.67 and 32.21 (­ CH2-CH2), 35.65 (­ CH2–C = N),
43.07 (–N–CH2), 43.76 (–CH–), 45.03 (–C–CH3), 47.76
(–C–(CH3)2), 52.71 (–OCH3), 61.45 ((–O–CH2), 115.80
and 140.90 (C = C), 154.58 (–S–C = N), 163.78 (C = N),
166.56 (–O–C = O), 182.46 (HN–C = O). Mass spectrum
(EI, 70 eV), m/z (Irel, %): 420 ­[M]+ (11), 392 (39), 287 (29),
186 (18), 134 (42), 55 (100). Found, %: C 57.09; H 6.28; N
9.73; S 7.93. ­C20H27N3O5S. Calculated, %: C 56.99; H 6.46;
N 9.97; S 7.61.
Methyl‑2‑(3‑(3‑bromopropyl)‑4‑oxo‑2‑((1,7,7‑tri‑
methylbicyclo[2.2.1]heptan‑2‑ylidene)hydrazono)
thiazolidin‑5‑ylidene)acetate (12)
A mixture of compound 3 (3.21  g, 0.01  mol) and
1,3-dibromopropane (1 ml, 0.01 mol) in 20 ml ethanol, in
presence of few drops of trimethylamine was refluxed until
the TLC (chloroform/methanol, 5:1) indicated the com-
plete consumption of the compound 3 (14 h). The reaction
mixture was let to stand overnight. The solid formed was
filtered, dried and crystallized from methanol as yellow pow-
der. Yield 3.55 g (78%), yellow powder, mp 80–82 °C. IR
(KBr) v/cm−1: 2953 ­(CHalkyl), 1706 (C = O), 1661 (C = N).
1
H NMR (400 MHz), ­CDCl3, δ (ppm): 0.80 (3H, s, ­CH3),
1.05 (3H, s, C ­ H3), 1.15 (3H, s, C­ H3), 1.25–1.96 (4H, m,
­CH2-CH2), 2.15 (1H, m, CH), 2.40 (2H, m, C ­ H2), 2.65 (2H,
m, N = C–CH2), 3.45 (2H, t, J = 7.0 Hz, ­CH2Br), 3.88 (3H, s,
­OCH3), 4.10 (2H, t, J = 9.2 Hz, N-CH2), 6.84 (1H, s, = CH).
Mass spectrum (EI, 70 eV), m/z (Irel, %): 457 [­ M]+ (6), 442
(2), 376 (100), 227 (66), 109 (46), 55 (87). Found, %: C
50.27; H 5.36; Br 17.73; N 9.06; S 7.06. ­C19H26BrN3O3S.
Calculated, %: C 50.00; H 5.74; Br 17.51; N 9.21; S 7.02.
General procedure for synthesis of compounds
(13a–e). Method (A)
A solution of compound 5 (3.5 g, 0.01 mol) and aromatic
amines (0.01 mol), namely aniline, p-methyl aniline, phe-
nylmethanamine, p-amino acetophenone and m-aminoben-
zoic acid in 25 ml toluene, in presence of t-Bu-OK (1.12 g,
0.01 mol) was refluxed till completion of the reaction moni-
tored by TLC (chloroform/methanol, 5:1). The reaction mix-
ture was concentrated under vacuum and (50 ml) water was
added to the residue with stirring, then (50 ml) chloroform
was added. The organic layer was collected, dried over anhy-
drous ­Na2SO4 and concentrated under reduced pressure to
leave a solid.
Method (B) A mixture of camphor thiosemcarbazone 1
(2.25 g, 0.01 mol) and N-aryl maleimides (0.01 mol), namely
N-phenyl maleimide, N-tolylmaleimide, N-benzyl maleim-
ide, N-(4-acetylphenyl) maleimide and N-(3-carboxyphenyl)
maleimide in 30 ml methanol with few drops of acetic acid
was refluxed till completion of the reaction monitored by
TLC (chloroform/methanol, 5:1). The reaction mixture was
allowed to stand overnight at room temperature, then the
solid formed was collected by filtration, dried and recrystal-
lized from methanol to yield compounds (13a–e).
2‑(4‑oxo‑2‑((1,7,7‑trimethylbicyclo[2.2.1]hep‑
tan‑2‑ylidene)hydrazono)thiazolidin‑5‑yl)‑N‑pheny‑
lacetamide (13a)
Yield (2.94 g, 3.46 g) (A:74%, B: 87%), white powder, mp
208- 210 °C. IR (KBr) v/cm−1: 3261 (NH), 3082 ­(CHarom),
2954 ­(CHalkyl), 1722 (C  =  O), 1619 (C  =  N). 1H NMR
(400 MHz), DMSO-d6, δ (ppm): 0.91 (3H, s, ­CH3), 0.94
(6H, s, 2­ CH3), 1.25–1.94 (4H, m, C
­ H2–CH2), 2.10 (1H, m,
CH),), 2.55 (2H, m, N = C–CH2), 2.85 (2H, d, J = 7.8 Hz,
13
 Journal of the Iranian Chemical Society

­CH2CO), 4.28 (1H, t, J = 6.2 Hz, SCH), 7.05–7.56 (5H, m, N‑(4‑acetylphenyl)‑2‑(4‑oxo‑2‑((1,7,7‑trimethylbi‑

aromatic), 10.06 (1H, s, NHPh, D ­ 2O exchangeable), 11.60 cyclo[2.2.1]heptan‑2‑ylidene)hydrazono)thiazoli‑
(1H, s,NH (thiazolidinone), ­D2O exchangeable). Mass spec- din‑5‑yl)acetamide (13d)
trum (EI, 70 eV), m/z (Irel, %): 398 [­ M]+ (54), 383 (2), 305
(12), 278 (100), 174), 77 (42). Found, %: C 63.74; H 6.26; Yield (3.39 g, 4.00 g) (A: 77%, B: 91%), colorless crys-
N 14.31; S 7.66. ­C21H26N4O2S. Calculated, %: C 63.29; H tals, mp 153–155 °C. IR (KBr) v/cm−1: 3278 (NH), 3108
6.58; N 14.06; S 8.04. ­(CHarom), 2958 (­ CHalkyl), 1671 (C = O), 1594 (C = N). 1H
NMR (400 MHz), DMSO-d6, δ (ppm): 0.71 (3H, s, C ­ H3),
0.90 (3H, s, C ­ H3), 0.95 (3H, s, C
­ H3), 1.18–1.90 (4H, m,
2‑(4‑oxo‑2‑((1,7,7‑trimethylbicyclo[2.2.1]
­CH2-CH2), 2.05 (1H, m, CH), 2.48 (2H, m, N = C–CH2),
heptan‑2‑ylidene)hydrazono)thiazo‑
2.53 (3H, s, ­COCH3) 2.99 (2H, d, J = 7.3 Hz, ­CH2CO), 4.30
lidin‑5‑yl)‑N‑(p‑tolyl)acetamide (13b)
(1H, t, J = 6.9 Hz, SCH), 7.69–7.94 (4H, d.d, aromatic),
10.43 (1H, s, NHPh, ­D2O exchangeable), 11.65 (1H, s, NH
Yield (3.21 g, 3.67 g) (A: 78%, B: 89%), white powder,
(thiazolidinone), ­D2O exchangeable). Mass spectrum (EI,
mp 163–165  °C. IR (KBr) v/cm −1: 3328 (NH), 3127
70 eV), m/z (Irel, %): 440 ­[M]+ (36), 425 (2), 305 (7), 278
­(CHarom), 2960 (­ CHalkyl), 1711 (C = O), 1615 (C = N). 1H
(100), 200 (67), 120 (45). Found, %: C 62.37; H 6.75; N
NMR (400 MHz), DMSO-d6, δ (ppm): 0.71 (3H, s, C ­ H3),
12.59; S 7.40. C ­ 23H28N4O3S. Calcd, %: C 62.70; H 6.41; N
0.73 (3H, s, ­CH3), 0.91 (3H, s, ­CH3), 1.25- 1.95 (4H, m,
12.72; S 7.28.
­2CH2), 2.11 (1H, m, CH), 2.28 (3H,s, ­CH3–Ph), 2.48 (2H,
m, = C–CH2), 3.19 (2H, d, J = 7.5 Hz, ­CH2CO), 4.30 (1H, t,
3‑(2‑(4‑oxo‑2‑((1,7,7‑trimethylbicyclohep‑
J = 6.8 Hz, SCH), 7.10–7.46 (4H, d.d, aromatic), 9.98 (1H,
tan‑2‑ylidene)hydrazono)thiazolidin‑5‑yl) aceta‑
s, NHPh, ­D2O exchangeable), 11.65 (1H, s,NH ( thiazolidi-
mido) benzoic acid (13e)
none), ­D2O exchangeable). Mass spectrum (EI, 70 eV), m/z
(Irel, %): 412 ­[M]+ (59), 397 (2), 305 (14), 278 (100), 107
Yield (3.62 g, 4.02 g) (A: 82%, B: 91%), white powder,
(46), 55 (37). Found, %: C 64.43; H 6.39; N 13.41; S 8.01.
mp 268–270  °C. IR (KBr) v/cm −1: 3377 (NH), 3118
­C22H28N4O2S. Calculated, %: C 64.05; H 6.84; N 13.58; S
­(CHarom), 2961 (­ CHalkyl), 1732 (C = O), 1606 (C = N). 1H
7.77.
NMR (400 MHz), DMSO-d6, δ (ppm): 0.70 (3H, s, C ­ H3),
0.90 (3H, s, C­ H3), 0.94 (3H, s, C­ H3), 1.20–1.92 (4H, m,
N‑benzyl‑2‑(4‑oxo‑2‑((1,7,7‑trimethylbicyclo[2.2.1]
­CH2-CH2), 2.02 (1H, m, CH), 2.51 (2H, m, N = C–CH2),
heptan‑2‑ylidene)hydrazono)thiazolidin‑5‑yl)aceta‑
2.99 (2H, d, J = 7.2 Hz, ­CH2CO), 4.30 (1H, t, J = 6.5 Hz,
mide (13c)
SCH), 7.43–7.79 (4H, m, aromatic), 8.23 (1H, s, NHPh,
­D2O exchangeable), 10.28 (1H, s, NH (thiazolidinone), ­D2O
Yield (3.13 g, 3.63 g) (A: 76%, B: 88%); white powder,
exchangeable), 12.25 (1H, s, COOH). 13C NMR (100 MHz),
mp 105–107  °C. IR (KBr) v/cm −1: 3305 (NH), 3064
DMSO-d6, δ(ppm); 11.26 ­(CH3), 18.53 and 19.29 (gem.
­(CHarom), 2956 (­ CHalkyl), 1717 (C = O), 1615 (C = N). 1H
­2CH3), 26.77 and 32.29 (­ CH2-CH2), 35.83 (­ CH2–C = N),
NMR (400 MHz), ­DMSOd6, δ (ppm): 0.73 (3H, s, ­CH3),
43.18 ­(CH2CO), 43.25 (–CH–), 47.41 (–S–CH), 47.44 (-C-
0.90 (3H, s, C ­ H3), 0.97 (3H, s, C
­ H3), 1.20–1.90 (4H, m,
CH3), 52.24 (–C–(CH3)2), 119.76, 123.14, 124.16, 129.08,
­CH2–CH2), 2.05 (1H, m, CH), 2.50 (2H, m, N = C-CH2),
131.30, 139.00 (Ar–C), 160.71 (–S–C = N), 167.08 (C = N),
2.99 (2H, d, J = 8.1 Hz, ­CH2CO), 3.28 (2H, s, C ­ H2Ph) 4.31
168.35 (COOH), 175.70 (NH-C = O), 177.34 (HN–C=O
(1H, t, J = 6.4 Hz, SCH), 7.23–7.32 (5H, m, aromatic-H),
(thiazolidinone ring)). Mass spectrum (EI, 70  eV), m/z
8.85 (1H, s, ­NHCH2, ­D2O exchangeable), 11.60 (1H, s, NH,
(Irel, %): 442 [­ M]+ (4), 427 (1), 278 (32), 217 (100), 183
thiazolidinone, ­D2O exchangeable). 13C NMR (100 MHz),
(45), 77 (29). Found, %: C 59.93; H 5.68; N 12.47; S 7.45.
DMSO-d6, δ(ppm); 11.27 ­(CH3), 18.56 and 19.30 (gem.
­C22H26N4O4S. Calcd, %: C 59.71; H 5.92; N 12.66; S 7.24.
­2CH3), 26.79 and 32.35 ­(CH2–CH2), 35.82 ­(CH2–C = N),
38.08 ­(CH 2CO), 42.17 (–CH–), 43.26 (–S–CH), 43.50
General procedure for synthesis of compounds
(–N–CH2), 47.44 (–C–CH3), 52.24 (–C–(CH3)2), 126.84,
14a,b
127.24, 128.28,139.16 (Ar–C), 160.71 (–S–C = N), 168.99
(C = N), 175.30 (NH–C = O), 177.34 (HN–C = O, thiazo-
A mixture of compound 5 (3.5 g, 0.01 mol) and hydrazines
lidinone ring). Mass spectrum (EI, 70 eV), m/z (Irel, %):
(0.01 mol), namely hydrazine hydrate and phenyl hydrazine
412 ­[M]+ (21), 397 (1), 278 (50), 150 (7), 91 (100), 55 (32).
in 25 ml ethanol, was refluxed till completion of the reac-
Found, %: C 64.37; H 6.32; N 13.36; S 8.19. C ­ 22H28N4O2S.
tion monitored by TLC (chloroform/methanol, 5:1). The
Calculated, %: C 64.05; H 6.84; N 13.58; S 7.77.
reaction mixture was allowed to stand overnight at room

13
Journal of the Iranian Chemical Society

temperature. The solid formed was collected by filtration, 2‑(4‑oxo‑2‑((1,7,7‑trimethylbicyclohep‑

dried and recrystallized from ethanol.
2‑(4‑oxo‑2‑((1,7,7‑trimethylbicyclohep‑
tan‑2‑ylidene)hydrazono)thiazolidin‑5‑yl)acetohy‑
drazide (14a)
Yield 2.80 g (83%), colorless crystals, mp 135–137 °C. IR
(KBr) v/cm−1: 3429–3228 (­ NH2, NH), 2953 (­ CHalkyl), 1666
(C = O), 1587 (C = N). 1H NMR (400 MHz), DMSO-d6,
δ (ppm): 0.69 (3H, s, ­CH3), 0.90 (3H, s, ­CH3), 0.99 (3H, s,
­CH3), 1.20–1.97 (4H, m, C­ H2-CH2), 2.05 (1H, m, CH), 2.51
(2H, m, N = C–CH2), 2.82 (2H, d, J = 7.4 Hz, ­CH2CO), 5.40
(1H, t, J = 6.3 Hz, SCH), 5.84 (2H, br, ­NH2), 8.05 (1H,NH,
­D2O exchangeable), 8.9 (1H, s, NH (thiazolidinone), D ­ 2O
exchangeable). Mass spectrum (EI, 70 eV), m/z (Irel, %): 336
­[M]+ (48), 320 (14), 292 (27), 227 (100), 106 (46), 55 (43).
Found, %: C 53.67; H 6.34; N 20.58; S 9.92. C ­ 15H23N5O2S.
Calculated, %: C 53.39; H 6.87; N 20.75; S 9.50.
tan‑2‑ylidene)hydrazono)thiazolidin‑5‑yl)‑N‑ pheny‑
lacetohydrazide (14b)
Yield 3.18 g (77%), yellow crystals, mp 238–240 °C. IR
(KBr) v/cm−1: 3238 (NH), 3082 (­ CHarom), 2955 (­ CHalkyl),
1723 (C = O), 1617 (C = N). 1H NMR (400 MHz), DMSO-
d6, δ (ppm): 0.75 (3H, s, ­CH3), 0.87 (6H, s, ­2CH3), 1.20–1.90
(4H, m, C ­ H 2-CH 2), 2.10 (1H, m, CH),), 2.50 (2H, m,
N = C-CH2), 2.90–2.15 (2H, d.d, J = 7.2, 5.2 Hz, ­CH2CO),
4.30 (1H, t, J = 6.5 Hz, SCH), 6.90–7.75 (5H, m, aromatic),
10.20 (1H, s,NH (thiazolidinone), ­D2O exchangeable). 13C
NMR (100 MHz), DMSO-d6, δ(ppm); 11.25 ­(CH3), 18.53
and 19.30 (gem. ­2CH3), 26.77 and 32.29 ­(CH2-CH2), 35.82
­(CH2-C = N), 37.50 (­ CH2CO), 42.14 (–CH–), 43.24 (-S-
CH), 47.41 (–C–CH3), 52.23 (–C–(CH3)2), 118.94, 119.03,
123.24, 128.77, 138.79 (Ar–C), 158.43 (–S–C = N), 168.01
(C = N), 175.30 (NH–C = O), 177.34 (HN–C = O (thiazoli-
dinone ring)). Mass spectrum (EI, 70 eV), m/z (Irel, %): 412
­[M]+ (3), 398 (47), 305 (11), 278 (81), 93 (79), 55 (100).
Found, %: C 61.12; H 6.39; N 16.79; S 7.96. C ­ 21H27N5O2S.
Calculated, %: C 60.99; H 6.58; N 16.94; S 7.75.

Scheme 1  Synthetic method of
camphor thiazolidinone 2, cam- BrCH2COOEt H
N O
phor thiazolidinylidene acetate N N
EtOH / CH3COONa , ,5h
3, thiazolidinyl acetic acid 4 and S
its ester 5 
2

O O
S
MeO OMe H
NNHCNH2 N O
N N
MeOH, rt, 2 h COOMe
1 S
3
O

O H
N O
N
Benzene , ,1h N COOH
S
4

EtOH H2SO4 , ,2h

H
N N O
N
S COOEt
5

13

Results and discussion
In this work, we tried to investigate the reactivity of camphor
thiosemicarbazone 1 toward different reagents. Thus, stir-
ring of compound 1 with dimethyl acetylene dicarboxylate
in methanol at room temperature afforded the corresponding
camphor thiazolidine acetate derivative 3 (Scheme 1). The
structure of 3 was confirmed by its spectral data. 1H-NMR
(δ ppm) spectrum of 3 revealed the presence of a broad sin-
glet signal at δ 11.55 ppm for the (NH), singlet signal at δ
6.89 ppm for the (C = CH) and at 3.88 ppm corresponding
to the methyl of ester group. In addition to, the signals cor-
responding to camphor protons. Moreover, the 13C NMR
spectrum showed sixteen different signals for sixteen differ-
ent carbons. The mass spectrum of 3 gave additional confir-
mation to its assigned structure, which showed molecular ion
peak ­(M+) at 335 corresponding to its formula.
On reaction of compound 1 with maleic anhydride as a
Michael acceptor reagent in benzene, the thiazolidinyl acetic
acid 4 was obtained (Scheme 1). The IR spectrum of com-
pound 4 showed the disappearance of ­(NH2, NH) bands and
appearance of absorption band at ν 1729 ­cm−1 correspond-
ing to the (C = O) group. The 1H-NMR (δ ppm) spectrum
revealed the presence of a broad signal at δ 13.1 ppm for
the (COOH), singlet for the (NH) at δ 9.72 ppm and sig-
nals at δ 2.96 and 4.21 ppm for the (­ CH2CO) and (­ SCH2)
protons, respectively. Moreover, the proposed structure of
compound 4 was completely fit with its 13C NMR spectrum
Scheme 2  Reaction of the
camphor thiazolidinone 2 with
different reagents
H N
N R
N N O N
S
2 , 4-6 h
13
Journal of the Iranian Chemical Society
(Experimental part). Also, the structure of 4 established
chemically via formation of the ester derivative 5 through
boiling with ethanol in the presence of sulfuric acid. The
1
H NMR (δ ppm) of compound 5 showed the disappear-
ance of carboxylic proton and appearance of quartet and
triplet signals at δ 4.09 and 1.17 ppm of ethyl carboxylate
protons. Also, the 13C NMR of compound 5 showed signals
at δ 14.01 and 60.58 ppm corresponding to carbons of ethyl
carboxylate group and the remaining carbons were detected
at their corresponding region.
Also, condensation of isatin and/or N-acetylisatin with
camphor thiazolidinone 2 in acetic acid/ sodium acetate
mixture gave the corresponding indolinone derivatives 6a
and 6b, respectively. The mass spectral data of 6a and 6b
confirmed their structures which showed molecular ion
peaks at 394 and 436 for 6a and 6b respectively for these
corresponding formulae. Also, the 1H NMR (δ ppm) of 6a
proved the presence of a singlet peak at δ 11.06 ppm cor-
responding to (NH isatin) proton and multiplet peaks at δ
6.92–8.84 ppm for the aromatic protons beside the disap-
pearance of the methylene protons of thiazolidinone ring,
while the 1H NMR data of 6b showed the presence of signals
at δ 6.90–8.88 ppm for the aromatic protons and a singlet
at δ 1.93 ppm for the acetyl group protons as well as disap-
pearance of the methylene protons of the thiazolidinone ring.
The chlorothiazole carbaldehyde 7 could be obtained via
formylation of 2 with phosphorus oxychloride in presence
of dimethyl formamide according to Vielsmier-Haack reac-
tion. The product was established by IR spectrum which
R
O N
O
O
S
O
N
ACOH / ACONa N H
6a, b
R: a= H, b= COCH 3
O
S
POCl3
N Cl
DMF,0 oC, 5 h N N
H
7
CH2=CHCN S
N O
EtOH / TEA N
N
,8h
8 CN
Journal of the Iranian Chemical Society

Scheme 3  Reaction of the cam- CN

phor thiazolidinylidene acetate ClCH2CN
3 with different reagents N O
EtOH / TEA N N
COOMe
, 20 h S
9

CN

CH2=CHCN
N O
EtOH / TEA N N
COOMe
,9h S
H 10
N O
N N
COOMe
S COOEt
3
ClCH2COOC2H5
N O
EtOH / NaOEt N N
COOMe
, 10 h S
11
Br

Br(CH2)3Br
N O
EtOH / TEA N N
COOMe
, 14 h S
12

showed absorption bands at ν 2790 and 1722 ­cm−1 due to
the groups (­ CHaldehyde) and (C = O), respectively. The 1H
NMR (δ ppm) spectrum of structure 7 showed a singlet sig-
nal at δ 9.71 ppm corresponding to proton of formyl group,
in addition the disappearance of the methylene protons of
the thiazolidinone ring.
Alkylation of thiazolidinone 2 at the nitrogen atom using
acrylonitrile in ethanol and presence of few drops of trieth-
ylamine, the thiazolidinyl propanenitrile derivative 8 was
obtained (Scheme 2). The chemical configuration of 8 was
established by their IR and 1H NMR spectra. The IR (­ cm−1)
showed the presence of absorption band at ν 2250 ­cm−1
corresponding to (CN) group. Furthermore, the 1H NMR
spectrum showed the signals of the (N-CH2CH2CN) group
at δ 3.92 and 2.92 ppm.
As well as, alkylation of the ester 3 at nitrogen atom
by using chloroaecetonitrile, acrylonitrile, ethylchloroac-
etate and 1,3-dibromopropane in basic conditions afforded
the N-alkyl derivatives 9, 10, 11 and 12, respectively
(Scheme 3). The IR ­(cm−1) spectra of 9 and 10 indicated
the presence of the (CN) function bands at ν 2250 and
2251  ­cm−1, respectively. Moreover, the 1H NMR spec-
tra of 9, 10, 11 and 12 showed the disappearance of NH
proton signal for all and appearance of singlet signal of
­(CH2CN) at δ 4.75 ppm for compound 9, triplets at δ 4.21
and 2.86 ppm of the (N–CH2CH2CN) function for compound
10, signals at δ 1.19 and 4.17 ppm of the ethyl carboxy-
late protons for 11 and signals at δ 2.40, 3.45 and 4.10 ppm
of ­(CH2CH2CH2-Br) protons for compound 12. The 13C
NMR spectra of 10 and 11 supported their structures. In
addition, the mass spectra and the elemental analysis of the
compounds 9, 10, 11 and 12 give strong evidence for their
assigned structures (Experimental part).
The amides 13a–e were synthesized through two routes;
the first one (route a) is by refluxing of the thiazolidine ace-
tate ester 5 with different aromatic amines such as aniline,
p-methylaniline, phenylmethanamine, p-amino acetophe-
none and m-aminobenzoic acid in toluene and presence of
potassium tertiary butoxide as catalyst. The reaction was
carried out through a nucleophilic attack of the amino group
on the carbonyl ester of 5 with elimination of ethanol mol-
ecule, while the second method (route b) is by the reaction
of camphor thiosemicarbazone 1 with N-phenylmaleimide,
N-tolylmaleimide, N-benzylmaleimide, N-(4-acetylphenyl)
maleimide and N-(3-carboxyphenyl) maleimidine in hot
methanol with of catalytic amount of acetic acid to furnish
13a-e in excellent yields (Scheme 4). The advantage of the
second route (b) over the first route (a) is for the higher yield
of (b), as illustrated in the experimental part.
The 1H NMR spectral data of the derivatives 13a–e
recorded signals corresponding to the aromatic protons for
all. The IR spectra of 13a–e detected the presence of bands
corresponding to the (CH-aromatic) functions for all struc-
tures. In addition, the mass spectral data and the elemental
analysis are completely compatible with the assigned struc-
tures. Moreover, the 13C NMR gave addition verification

13
 Journal of the Iranian Chemical Society

Scheme 4  Reaction of the
thiazolidinyl acetic acid ester 5
with different reagents

to the structure of 13c and 13e, which showed twenty-two
different signals for twenty-two different carbon atoms for
both 13c and 13e (Experimental part).
Finally, refluxing the ethanolic solution of compound
5 with hydrazine hydrate and/or phenyl hydrazine yielded
the hydrazides 14 and 15,, respectively (Scheme 4). The
IR of structure 14a showed characteristic bands at ν 3429
and 3229 ­cm−1 corresponding to (­ NH2) and (NH) groups.
In addition, the 1H NMR spectra of 14a and 14b showed
the disappearance of ethyl carboxylate protons for both and

Table 1  Diameter of inhibition Sample no Bacterial and fungal growth inhibition zone diameter (mm)/% Activity index
zone (mm) of the tested
compounds E. coli Bacillus subtilis C. Albicans A. flavus

4 11 42.3 15 65.2 14 51.8 19 76

5 3 11.5 8 34.8 6 22.2 14 56
6a NA – 5 21.7 4 14.8 7 28
8 10 38.5 14 60.9 13 48.1 12 48
9 NA – 4 17.4 2 7.4 5 20
10 NA – 2 8.7 NA – NA –
12 13 50 17 73.9 18 66.7 21 84
13d NA – NA – NA – 2 8
13e 5 19.2 10 43.5 9 33.3 10 40
14b 7 26.9 12 52.2 10 37 11 44
Ampicillin 26 100 23 100 NA – NA –
Clotrimazole NA – NA – 27 100 25 100

NA no activity

13
Journal of the Iranian Chemical Society
%
100
Acvity 80
index
60
E.coli
Bacillus sublis
40
C. Albicans
20
A. flavus
0 Structure–activity correlation
Fig. 2  The effect of the selected compounds against the bacteria and
fungi
appearance signals at δ 5.84 and 8.05 ppm corresponding
to ­(NH2) and (NH) groups, respectively, for the hydrazide
14a, and appearance of signals of aromatic protons at
6.90–7.75 ppm. Moreover, the 13C NMR spectrum of com-
pound 14b gave additional evidence for the proposed struc-
ture, which showed the presence of twenty-one different
signals for 21 carbons.
Antimicrobial test
The antimicrobial effect of some thiazolidinones has been
previously studied. Pitta E. et al. [29] studied the effect of
some thiazolidinones against E. coli and C. albicans, which
exhibited low inhibition against E. coli and high inhibition
against C. albicans. Also, Mishra I. et al. [30] investigated
the antimicrobial activity of some prepared thiazolidinone
derivatives against E. coli, A. flavus and C. albicans and
these derivatives showed high inhibition effect for all. Fur-
thermore, the in vitro evaluation of some thiazolidine-4-ones
made by Patel H. et al. [31] showed that the screened com-
pounds inhibit the growth of the tested microorganisms.
In our work, the antimicrobial effect of the selected new
thiazolidinones 4, 5, 6a, 8–10, 12, 13d, 13e and 14b on two
bacterial species (gram positive bacteria (Bacillus subti-
lis) and gram negative bacteria (Escherichia coli)) and two
mycol species (Candida albicans and Aspergillus flavus)
was carried out using filter paper disc method [32]. The
Bacillus subtilis, E. coli, Candida albicans and Aspergillus
flavus were incubated at 37 °C for 24 h and every test was
repeated three times. As positive controls, standard solutions
of Ampicillin and Clotrimazole were chosen as antibacterial
agent and as antifungal agent, respectively. The recorded
Fig. 3  Camphor thiazolidinone
structures of higher activity
H S
N O
N N
N COOH
S COOMe
4 8
results for each tested sample were represented as the aver-
age diameter of inhibition zones (IZ) of bacterial or fungal
growth around the discs in mm as listed in Table 1.
The following graph shows the effectiveness of the tested
compounds against the chosen bacteria and fungi (Fig. 2).
The obtained results in Table 1 revealed that some cross-
functional side chain play an important role in the effec-
tiveness potential for the tested compounds. Thus, in case
of compound 12, the presence of bromine atom in the
molecule has an oxidative effect on the amino acid resi-
due of outer membrane cell protein, while the presence of
the cyano alkyl side chain in compounds 8, 9 or 10 has a
high, moderate or weak effect, respectively, on metabo-
lism of bacterial or fungi cells depending on the length
of carbon chain and presence or absence of the carboxy
methyl group in the molecule. On the other hand, the
presence of the carboxylic group in compound 4 encour-
ages the binding of the molecule in the sites of protein
surface membrane along with the amino acids residue
and this enhancing its activity, while its ester 5 has lower
binding effect. Also, in compound 13e a moderate effect
appeared due to binding of the carboxylic group, while
13d hasn’t carboxylic group (Nearly zero effect). Com-
pound 14b gave a moderate effect, may be due to binding
with the carboxylic group of the protein amino acid resi-
due through its three (NH) groups [33] (Fig. 3).
Obviously, the new tested camphor thiazolidinones
possessed a wide spectrum inhibition against the used
species of bacteria and fungi at the same time, in compar-
ing with the previous studies of the antimicrobial activity
of other thiazolidinone compounds against the same types
of bacteria and fungi.
Conclusion
In summary, a series of new camphor thiazolidinone deriv-
atives 3-14a,b have been synthesized based on camphor
thiosemicarbazone 1 as a precursor. The configurational
structure of the synthesized compounds was confirmed by
their elemental analysis and spectral data. Compounds 4, 5,
6a, 8–10, 12, 13d, 13e and 14b were selected and screened
Br
O
N O N
N N N
S
CN 12
13

against two different kinds of bacteria (Bacillus subtilis) and
(Escherichia coli), as well as two different kinds of fungi
(Candida albicans) and (Aspergillus flavus) by filter paper
disc method. Compounds 4, 8, and 12 showed a higher activ-
ity than the others against all bacteria and fungi used. The
results are promising and show that the fine tuning of the
structure 12 could lead to a new antibacterial or antifungal
agent in treating microbial infections.
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Authors and Affiliations
Ahmed M. Abo‑Bakr1   · Entesar A. Hassan1 · Al‑Hassan S. Mahdy1 · Salem E. Zayed1
1
* Ahmed M. Abo‑Bakr
ahmadbaker672@sci.svu.edu.eg
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3970
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Department of Chemistry, Faculty of Science, South Valley
University, Qena 83523, Egypt
13