Effect of iodine on the antimicrobial activity of new spiro and isolated β-Lactam thiazolidinone derivatives

Article abstract of DOI:10.1080/10426500601149929

The reaction of 1,4-naphthoquinone with a mixture of urea and ethylcyanoacetate in ethanol containing a piperidine catalyst afforded compound 1, which reacted with acetonitrile and steam of hydrogen chloride to yield compound 2, which readily condensed with different aromatic amine to give 3a-c. Compound 3a-c reacted with chloroacetyl chloride and/or mercaptoacetic acid to give spiro β-Lactam 4a-c, and spiro thiazolidinone 5a-c also isolated β-Lactam and thiazolidinone 7a-d and 8a-d prepared from a reaction of isolated schiff base 6a-d with chloroacetyle chloride and mercaptoacetic acid. Compound 2 reacted with ethyl iodide to give compound 9, which used to synthesis of new shiff bases 10a-c and13a-d. The new schiff bases 10a-c and 13a-d reacted with chloroacetyl chloride or mercaptoacetic acid to give B-Lactams 11a-c and 14a-d and thiazolidinone derivatives 12a-c and 15a-d.

Full text of DOI:10.1080/10426500601149929

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Phosphorus, Sulfur, and Silicon
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Effect of Iodine on the
Antimicrobial Activity of New
Spiro and Isolated β-Lactam
Thiazolidinone Derivatives
N. A. A. El-Kanzi a , A. K. Khalafallah a & M. Younis b
a Chemistry Department , Faculty of Science ,
Aswan, Egypt
b Botany Department , Faculty of Science , Aswan,
Egypt
Published online: 19 Apr 2007.
To cite this article: N. A. A. El-Kanzi , A. K. Khalafallah & M. Younis (2007)
Effect of Iodine on the Antimicrobial Activity of New Spiro and Isolated β-Lactam
Thiazolidinone Derivatives, Phosphorus, Sulfur, and Silicon and the Related Elements,
182:5, 1163-1181, DOI: 10.1080/10426500601149929
To link to this article: http://dx.doi.org/10.1080/10426500601149929
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Phosphorus, Sulfur, and Silicon, 182:1163–1181, 2007
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500601149929
Effect of Iodine on the Antimicrobial Activity of New
Spiro and Isolated β-Lactam Thiazolidinone Derivatives
N. A. A. El-Kanzi
A. K. Khalafallah
Chemistry Department, Faculty of Science, Aswan, Egypt
M. Younis
Botany Department, Faculty of Science, Aswan, Egypt
The reaction of 1,4-naphthoquinone with a mixture of urea and ethylcyanoacetate in
ethanol containing a piperidine catalyst afforded compound 1, which reacted with
acetonitrile and steam of hydrogen chloride to yield compound 2, which readily
condensed with different aromatic amine to give 3a–c. Compound 3a–c reacted
with chloroacetyl chloride and/or mercaptoacetic acid to give spiro β-Lactam 4a–
c, and spiro thiazolidinone 5a–c also isolated β-Lactam and thiazolidinone 7a–d
and 8a–d prepared from a reaction of isolated schiff base 6a–d with chloroacetyle
chloride and mercaptoacetic acid. Compound 2 reacted with ethyl iodide to give
compound 9, which used to synthesis of new shiff bases 10a–c and13a–d. The new
schiff bases 10a–c and 13a–d reacted with chloroacetyl chloride or mercaptoacetic
acid to give B-Lactams 11a–c and 14a–d and thiazolidinone derivatives 12a–c
and 15a–d.
Keywords Spiro B lactam, spiro thiazolidinone, shief base
INTRODUCTION
The explosive interest in β-Lactams and related derivatives stems
from the fact that some monocyclic β-Lactams exhibit antibacterial ac-
tivities. Some examples comprise of the naturally occuring monobac-
tams and nocardicins.1 Contrary to penicillins, cephalosporins, or no-
cardicins, monobactams were not produced by fungi or actinomycetes,
but from bacteria, for example, Bacillus pseudomonas.2 Nocardicins
proved the relationship with cephalosporins and penicillins via the cor-
responding β-configuration at C(3), but they have no therapeutic sig-
nificance. Synthetic oxamazins,3−5 thiamazins,6 and monosulfactams7
showed some antibacterial activity, which raised again a major interest
Received December 4, 2004; accepted October 19, 2006.
Address correspondence to N. A. A. El-Kanzi, Chemistry Department, Faculty of Sci-
ence, South Valley University, Aswan, Egypt. E-mail: kanzi2nour@yahoo.com
1163

1164
N. A. A. El-Kanzi et al.
in the area of 2-azetidinone chemistry. Also thiazole derivatives such
as pencillins, which have fused thiazolidine and β-Lactam rings, were
known and used as potent antibiotics.8
RESULTS AND DISCUSSION
Our initial strategy in this research project for the synthesis of dif-
ferent structural formulas corresponding to the isolated, spiro, and
fused systems depended upon the synthesis of the new fused 2,4-
diamino-5, 10-dioxo-1,5,10,11-tetrahydrobenz[g]quinoline-3-ethyl car-
boxylate 1, which was synthesized by a cycloaddition reaction of
equimolecular ratios of the appropriate urea and ethylcyano acetate
with 2 mole of 1,4-naphthoquinone (one mole used as an oxidizing
agent), in ethanol containing piperidine as catalyst. At first our the-
ortical conception of the obvious cycloaddition reaction led to the for-
mation of compound 1, but the expermental evidence that depends on
the different types of analysis to the reaction product proved that the
cycloaddition reaction leads to the formation of compound 1 through the
electronic cyclization according to the suggested mechanism (Scheme 1
illustrates the formation of compound 1).
The structure of the new synthesized compound 1 was confirmed by
its elemental analysis and IR which revealed a carbonyl group of ester
at 1745 cm−1 and 1H NMR spectra, which revealed the presence of NH
group at δ 11.02, NH2 group at δ 6.82, NH2 group at δ 4.53, a triplet at δ
1.23 assigned for methyl group, and quartet at δ 3.55 for CH2 group. The
mass spectrum showed the molecular ion peak (M+, C16H15O4N3) at mz
313. The inteligible bases of 1H NMR led us to descide that the isolable
structural formula produced from the reaction of the appropriate urea
and malononitrile with 1,4-naphthoquinone is the structural formula of
compound 1 because of the appearance of the signal at δ 3.21 as a result
of the fussion of 1,4-naphthoquinone with the unsaturated substituted
piperidine ring.
Compound 2 was prepared by the reaction of compound 1 and ace-
tonitrile with a stream of dry hydrogen chloride gas in the presence
of dioxane for about 12 h, and the reaction mixture was heated on a
water bath for 2 h after passing hydrogen chloride gas. The structure of
the new synthesized compound 2 was confirmed by its elemental anal-
ysis and IR spectra, which revealed a signal of the carbonyl group at
1
1680 cm−1 and H NMR spectra, which revealed the presence of NH
group at δ 10.56, NH2 group at δ 6.81, singlet signal at 1.25 for the
methyl group. The absence of the signals assigned for the ethyl group
indicate the structure of compound 2; the mass spectrum showed the
molecular ion peak (M+, C16H12O3N4) at m/z 308.

1165

1166
N. A. A. El-Kanzi et al.
Compound 2 underwent a fussion reaction with ethyl iodide to give
compound 9. The structure of compound 9 was confirmed by their ele-
mental analysis, IR, 1H NMR spectra, and mass spectra (cf. Table I, II,
and III).
It is very important to know that the formation of Schiff bases corre-
sponding to the newly heterocyclic compounds is the cornerstone in the
synthesis of the corresponding spiro and isolated β-Lactams and thi-
azolidinone compounds. The activity of the carbonyl group in position
4 and also the activity of the methyl group at C2 render compound 2
to react with different aromatic amine and different nitroso compound
to give new Schiff bases 3a–c and 6a–d. The structures of these newly
synthesized Schiff bases 3a–c and 6a–d were confirmed by their ele-
1
mental analysis, IR, H NMR, and mass spectra (cf. Tables I, II, and
III.) The activity of the azamethine center in compound 3a–c is more
avaliable than the activity of the NH group toward the addition process
of chloroacetyl chloride, and this mentioned phenomena is due to the
presence of the π electron, which makes the foundation of the δ positive
and δ negative charge on the carbon and nitrogen atom, respectively,
more easy than the presence of this phenomena on the NH group in
which the bonding between nitrogen and hydrogen wheather strong
according to the nature of this bonding which leads to decreasing of the
mobility desire of the hydrogen atom of this NH group. Thus compound
3a–d reacted with chloroacetyl chloride or mercaptoacetic acid to give
spiro β-Lactams and spiro thiazolidinone compounds9 4a–c and 5a–c.
The structures of these spiro compounds 4a–c and 5a–c were confirmed
by their elemental analysis, IR, 1H NMR and mass spectra (cf. Tables I,
II, III). The formation of spiro azitidine derivatives 4a–c was suggested
to proceed according to the following mechanisms (Scheme 2).
It is reported that β-Lactams play a vital role in medicinal chemistry
as a key intermediate for the synthesis of penicillin, cephalosporins, and
their analogs. On the other hand, thiazolidinones derivatives are used
in biological activities such as bactericidal, pesticidal, and fungicidals,
insecticidal activities.10,11 Thus the activity of azamethine center in
compound 6a–d renders it avaliable to react with chloroacetyl chloride
and/or mercaptoacetic acid to give new isolated β-Lactams and thiazo-
lidinone compounds 7a–d and 8a–d. The structures of compounds 7a–d
and 8a–d were confirmed by their elemental analysis, IR, 1H NMR and
mass spectra [cf. Tables 1,2,3].
The application of heterocyclic compounds in various aspects is be-
yond estimation, and there is always continuous need for the discovery
of new heterocyclic compounds, which are used in industrial and various
biological fields. Thus we used the new compound 9 in the synthesis of
spiro and isolated β-lactams and thiazolidinone compounds. Compound

Thiazolidinone Derivatives
1167
TABLE I
Compound
No.
Crystal
solvent
Yield %
M.P.
Mol. formula
(Mol. Wt)
MS
1
2
3a
3b
3c
4a
4b
4c
5a
5b
5c
6a
6b
6c
6d
7a
7b
7c
7d
8a
8b
8c
8d
9
10a
10b
10c
11a
11b
11c
12a
12b
12c
13a
13b
13c
13d
14a
14b
14c
14d
15a
15b
15c
15d
75
65
63
60
66
70
69
73
75
72
74
67
68
70
66
69
68
65
77
76
74
73
72
75
72
73
70
70
71
73
69
70
72
73
71
69
68
70
72
69
71
69
67
70
68
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
C16H15O4N3
C16H12O3N4
C22H17O2N5
C22H17O3N5
(313.31)
(308.30)
(383.41)
(399.41)
(414.40)
(459.90)
(475.90)
(490.89)
(457.51)
(473.51)
(488.50)
(463.37)
(463.37)
(413.39)
(440.46)
(539.94)
(539.94)
(489.88)
(516.87)
(537.55)
(537.55)
(487.49)
(514.56)
(464.26)
(549.45)
(565.45)
(580.44)
(615.86)
(631.86)
(646.85)
(613.47)
(629.47)
(644.46)
(619.41)
(619.41)
(569.35)
(596.42)
(695.90)
(695.90)
(645.84)
(672.91)
(693.51)
(693.51)
(743.45)
(670.52)
313
308
383
399
414
459
475
490
457
473
488
463
463
413
440
539
539
489
516
537
537
487
514
464
549
565
580
615
631
646
613
629
644
619
619
569
596
695
695
645
672
693
693
743
670
C
22H16O4N5
C24H18O3N5Cl
C24H18O4N5Cl
C24H17O5N5Cl
C24H19O3N5S
C
24H19O4N5S
C24H18O5N5S
C26H17O4N5
C26H17O4N5
C22H15O4N5
C
24H20O3N6
C28H18O5N5Cl
24H18O5N5Cl
C24H16O5N5Cl
C26H21O4N6Cl
C
C28H19O5N5S
C28H19O5N5S
C
24H17O5N5S
C26H22O4N6S
C18H17O3N4I
C24H32O2N5I
C24H32O3N5I
C
24H31O4N5I
C26H23O3N5ClI
26H23O4N5ClI
C
C26H22O5N5ClI
C26H24O3N5SI
C
26H24O4N5SI
C26H23O5N5SI
C28H22O4N5I
C
28H22O4N5I
C24H20O4N5I
26H25O3N6I
C30H23O5N5ClI
30H23O5N5ClI
C
C
C26H21O5N5ClI
C28H26O4N6ClI
C
30H24O5N5SI
C30H24O5N5SI
26H22O5N5SI
C28H27O4N6SI
C

1168
N. A. A. El-Kanzi et al.
TABLE II
Compound No.
1
1H NMR (DMSO) ppm
δ1.23(t, CH3), δ 3.55(q, CH2), δ 4.53(s, NH2), 6.82(s, NH2), δ 11.02(s,
NH), 8.1–7.02(m, 5H aromatic hydrogen)
2
δ1.25(s, CH3), δ 6.81(s, NH2), δ 10.56(brs, NH), 8.01–7.1(m,7H
aromatic protons)
3a
3b
3c
4a
4b
4c
5a
5b
5c
δ1.24(s, CH3), δ 6.79(s, NH2), δ 10.55(brs, NH), 8.1–7.01(m, 11H
aromatic protons)
δ1.259(s, CH3), δ 6.77(s, NH2), δ 10.56(brs, NH), 8.1–7.01(m, 11H
aromatic protons)
δ1.26(s, CH3), δ 6.78(s, NH2), δ 10.57(brs, NH), 8.1–7.01(m, 10H
aromatic protons)
δ1.24(s, CH3), δ 6.75(s, NH2), δ 10.43(brs, NH), 8.1–7.01(m, 12H
aromatic protons)
δ1.23(s, CH3), δ 6.73(s, NH2), δ 10.44(brs, NH), 8.1–7.01(m, 12H
aromatic protons)
δ1.24(s, CH3), δ 6.74(s, NH2), δ 10.45(brs, NH), 8.1–7.01(m, 11H
aromatic protons)
δ1.24(s, CH3), 2.5(s, CH2 protons), δ 6.76(s, NH2), δ 10.55(brs, NH),
8.1–7.01(m, 10H aromatic protons)
δ1.23(s, CH3), 2.5(s, CH2 protons), δ 6.75(s, NH2), 10.54(brs, NH),
8.1–7.01(m, 10H aromatic protons)
δ1.24(s, CH3), 2.5(s, CH2 protons), δ 6.75(s, NH), 10.54(brs, NH),
8.1–7.01(m, 9H aromatic protons)
6a
6b
6c
6d
δ6.75(s, NH2), δ 10.25(brs, NH), δ 8.1–7.01(m, 14H aromatic protons)
δ6.73(s, NH2), δ 10.26(brs, NH), 8.1–7.01(m, 14H aromatic protons)
δ6.69(s, NH2), δ 10.27(brs, NH), 8.1–7.01(m, 12H aromatic protons)
δ1.25(ds, 2CH3), δ 6.66(s, NH2), δ 10.26(brs, NH), 8.1–7.01(m, 11H
aromatic protons).
7a
7b
7c
7d
δ6.65(s, NH2), δ 10.23(brs, NH), 8.1–7.01(m, 15H aromatic protons)
δ6.67(s, NH2), δ 10.24(brs, NH), 8.1–7.01(m, 15H aromatic protons)
δ6.66(s, NH2), 10.25(brs, NH), 8.1–7.01(m, 13H aromatic protons)
δ1.23(ds, 2CH3), δ 6.65(s, NH2), 10.25(brs, NH), 8.1–7.01(m, 15H
aromatic protons)
8a
δ2.5(s, CH2 of thiazolidinone), δ 6.6(s, NH2), δ 10.26(brs, NH),
8.1–7.01(m, 14H aromatic protons)
8b
δ2.5(s, CH2 of thiazolidinone), δ 6.65(s, NH2), δ 10.25(brs, NH),
8.1–7.01(m, 14H aromatic protons)
8c
δ2.5(s, CH2 of thiazolidinone), δ 6.64(s, NH2), δ 10.23(brs, NH),
8.1–7.01(m, 12H aromatic protons)
8d
9
δ1.23(ds, 2CH3), δ 2.5(s, CH2 of thiazolidinone), δ 6.66(s, NH2),
10.25(brs, NH), 8.1–7.01(m, 11 aromatic protons)
δ1.1(t, CH3), δ 1.25(s, CH3), δ 3.35(q, CH2), δ 6.67(s, NH2), δ
10.35(brs, NH), 8.1–7.01(m, 6H aromatic protons)
δ1.12(t, CH3), δ 1.24(s, CH3), δ 3.36(q, CH2), δ 6.65(s, NH2), δ
10.36(brs, NH), 8.1–7.01(m, 21 aromatic protons)
δ1.11(t, CH3), δ 1.23(s, CH3), δ 3.35(q, CH2), δ 6.66(s, NH2), δ
10.35(brs, NH), 8.1–7.01(m, 21H aromatic protons)
δ1.12(t, CH3), δ 1.24(s, CH3), δ 3.37(q, CH2), δ 6.67(s, NH2),
10.34(brs, NH), 8.1–7.01(m, 20H aromatic protons)
(Continued on next page)
10a
10b
10c

Thiazolidinone Derivatives
1169
TABLE II (Continued)
Compound No.
1H NMR (DMSO) ppm
11a
11b
11c
12a
δ1.11(t, CH3), δ 1.23(s, CH3), δ 3.36(q, CH2), δ 6.68(s, NH2),
10.36(brs, NH), 8.1–7.01(m, 12H aromatic protons)
δ1.12(t, CH3), δ 1.24(s, CH3), 3.35(q, CH2), δ 6.67(s, NH2), 10.35(brs,
NH), 8.1–7.01(m, 12H aromatic protons)
δ1.11(t, CH3), δ 1.23(s, CH3), 3.35(q, CH2), δ 6.68(s, NH2), 10.35(brs,
NH), 8.1–7.01(m, 13H aromatic protons)
δ1.12(t, CH3), δ 1.23(s, CH3), δ 2.5(s, CH2 of thiazolidinone), δ 3.35(q,
CH2), δ 6.65(s, NH2), 10.33(brs, NH), 8.1–7.01(m, 11H aromatic
protons)
12b
12c
δ1.1(t, CH2), δ 1.23(s, CH3), δ 2.5(s, CH2 of thiazolidinone), δ 3.36(q,
CH2), δ 6.66(s, NH2), 10.34(brs, NH), 8.1–7.01(m, 11H aromatic
protons)
δ1.12(t, CH3), δ 1.22(s, CH3), δ 2.5(s, CH2 of thiazolidinone), δ 3.33(q,
CH2), δ 6.65(s, NH2), 10.35(brs, NH), 8.1–7.01(m, 10H aromatic
protons)
13a
13b
13c
13d
14a
14b
14c
14d
15a
15b
15c
15d
δ1.12(t, CH3), δ 3.35(q, CH2), δ 6.66(s, NH2), 10.36(brs, NH),
8.1–7.01(m, 14H aromatic protons)
δ1.11(t, CH3), δ 3.34(q, CH2), δ 6.65(s, NH2), 10.35(brs, NH),
8.1–7.01(m, 14H aromatic protons)
δ1.12(t, CH3), δ 3.35(q, CH2), δ 6.67(s, NH2), 10.36(brs, NH),
8.1–7.01(m, 12H aromatic protons)
δ1.12(t, CH3), δ 1.25(s, 2CH3), δ 3.36(q, CH2), δ 6.66(s, NH2),
10.35(brs, NH), 8.1–7.01(m, 17H aromatic protons)
δ1.12(t, CH3), δ 3.35(q, CH2), δ 6.65(s, NH2), 10.33(brs, NH),
8.1–7.01(m, 15H aromatic protons)
δ1.11(t, CH3), δ 3.36(q, CH2), δ 6.66(s, NH2), 10.35(brs, NH),
8.1–7.01(m, 15H aromatic protons)
δ1.1(t, CH3), δ 3.35(q, CH2), δ 6.64(s, NH2), 10.34(brs, NH),
8.1–7.01(m, 13H aromatic protons)
δ1.12(t, CH3), δ 1.23(s, 2CH3), δ 3.36(q, CH2), δ 6.65(s, NH2),
10.35(brs, NH), 8.1–7.01(m, 12H aromatic protons)
δ1.12(t, CH3), δ 2.5(s, CH2 of thiazolidinone), δ 3.34(q, CH2), δ 6.67(s,
NH2), 10.36(brs, NH), 8.1–7.01(m, 12H aromatic protons)
δ1.11(t, CH3), δ 2.5(s, CH2 of thiazolidinone), δ 3.35(q, CH2), δ 6.66(s,
NH2), 10.33(brs, NH), 8.1–7.01(m, 12H aromatic protons)
δ1.05(t, CH3), δ (s, CH2 of thiazolidinone), δ 3.36(q, CH2), δ 6.64(s,
NH2), 10.34(brs, NH), 8.1–7.01(m, 14H aromatic protons)
1.12(t, CH3), 1.24(s, 2CH3), δ 2.5(s, CH2 of thiazolidinone), δ 3.35(q,
CH2), δ 6.66(s, NH2), 10.36(brs, NH), 8.1–7.01(m, 11H aromatic
protons)
9 was prepared by the reaction of compound 2 with ethyl iodide, which
was heated together under fussion for 1 h. The structure of compound
9 was confirmed by elemental analysis, IR spectra, and 1H NMR which
reaveled the presense of a singlet signal for the methyl group at δ 1.25,
a quarted signal at 3.45 for CH2, and a triplet signal at 1.02 for the

1170
N. A. A. El-Kanzi et al.
TABLE III
(Calcd.) Found
Compound
No.
IR υmax/cm−1
C
H
N
S
Cl
1
3400–3100(NH, NH2), 1745 (C
ester), 1645 (C O)
3400–3150(NH, NH2), 1685(C O),
1660(C O)
3400–3100(NH, NH2), 1665(C O),
1585(C N)
3400–3100(NH, NH2, OH), 1660(C O), (66.16) (4.29) (17.53)
1590(C N)
3400–3100(NH, NH2), 1650(C O),
1580(C N)
O
(61.34) (4.83) (13.41)
—
—
—
—
—
—
—
—
-
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
-
61.30 4.78 13.39
(62.34) (3.92) (18.17)
62.29 3.89 18.13
(68.92) (4.47) (18.27)
68.88) 4.42 18.23
2
3a
3b
3c
4a
4b
4c
5a
5b
5c
6a
6b
6c
66.13 4.25 17.49
(63.77) (3.89) (16.90)
63.73 3.86 16.86
(62.68) (3.95) (15.23)
62.65 3.91 15.19
—
3400–3100(NH, NH2), 1655(C O)
(7.71)
7.58
(7.45)
7.41
(7.22)
7.19
—
—
—
—
—
—
—
—
—
—
—
—
3450–3100(NH, NH2, OH), 1665(C O) (60.57) (3.81) (14.72)
60.52 3.78 14.68
3400–3100(NH, NH2), 1660(C O)
(58.72) (3.49) (14.27)
58.69 3.45 14.23
(63.01) (4.19) (15.31) (7.01)
62.99 4.18 15.29 6.98
3400–3150(NH, NH2), 1650(C O)
3450–3100(NH, NH2, OH), 1655(C O) (60.88) (4.04) (14.79) (6.77)
60.83 4.01 14.75 6.74
3400–3150(NH, NH2), 1650(C O)
(59.01) (3.71) (14.34) (6.56)
58.98 3.68 13.99 6.52
3450–3100(NH, NH2, OH), 1670(C O), (67.38) (3.70) (15.11)
1595(C N) 67.34 3.67 15.07
3450–3100(NH, NH2, OH), 1675(C O), (67.38) (3.70) (15.11)
1585(C N) 67.35 3.65 15.05
3450–3100(NH, NH2, OH), 1660(C O), (63.92) (3.66) (16.94)
—
—
—
—
—
—
1590(C N)
63.88 3.62 16.90
6d
3450–3100(NH, NH2), 1655(C O),
1580(C N)
(65.45) (4.58) (19.08)
65.41 4.53 19.04
—
—
—
—
7a
7b
7c
7d
8a
8b
3450–3100(NH, NH2, OH), 1660(C O) (62.29) (3.36) (12.97)
62.26 3.32 12.93
—
—
—
—
—
—
—
—
(6.57)
6.54
(6.57)
6.52
(7.24)
7.19
6.86
6.82
—
3400–3100(NH2NH2, OH),
1690–1660(C O)
3400–3100(NH, NH2, OH),
1717–1665(C O)
3400–3100(NH, NH2),
1718—1660(C O)
(62.29) (3.36) (12.97)
62.25 3.31 12.92
(58.84) (3.29) (14.30)
58.81 3.24 14.26
(60.40) (4.10) (16.27)
60.35 3.97 3.97
3400–3100(NH, NH2, OH),
1717–1655(C O)
3450–3100(NH, NH2, OH),
1720–1660(C O)
(62.56) (3.56) (13.03) (5.94)
62.51 3.53 12.99 5.90
(62.56) (3.56) (13.03) (5.94)
62.53 3.52 12.97 5.89
—
—
—
(Continued on next page)

Thiazolidinone Derivatives
1171
TABLE III (Continued)
(Calcd.) Found
Compound
No.
IR υmax/cm−1
3400–3100(NH, NH2, OH),
1717–1665(C O)
3400–3100(NH, NH2),
1720–1655(C O)
C
H
N
S
Cl
8c
(59.13) (3.52) (14.37) (6.58)
59.09 3.49 14.33 6.54
(60.69) (4.31) (16.33) (6.23)
60.64 4.28 16.29 6.19
—
—
–
8d
—
9
3400–3100(NH, NH2), 1680(C O),
1655(C O)
3450–3100(NH, NH2), 1686(C O),
1590(C N)
3450–3100(NH, NH2, OH), 1680(C O), (50.98) (5.70) (12.39)
1580(C N)
3400–3100(NH, NH2), 1685(C O),
1590(C N)
3450–3100(NH, NH2),
1725–1655(C O)
3450–3100(NH, NH2, OH),
1720–1660(C O)
3400–3100(NH, NH2),
1725—1650(C O)
3400–3100(NH, NH2),
1730–1660(C O)
3450–3100(NH, NH2, OH),
1725–1655(C O)
3400–3100(NH, NH2),
1720—1650(C O)
3450–3100(NH, NH2, OH), 1675(C O), (54.30) (3.58) (11.31)
1587(C N) 54.27 3.54 11.28
3450–3100(NH, NH2, OH), 1665(C O), (54.30) (3.58) (11.31)
1589(C N) 54.26 3.52 11.26
3450–3100(NH, NH2, OH), 1670(C O), (50.63) (3.54) (12.30)
1585(C N)
3400–3100(NH, NH2), 1668(C O),
1590(C N)
3450–3100(NH, NH2, OH),
1717–1650(C O)
3450–3100(NH, NH2, OH),
1720–1655(C O)
34540–3100(NH, NH2, OH),
1725–1660(C O)
3400–3100(NH, NH2),
1720–1655(C O)
3450–3100(NH, NH2, OH),
1720–1666(C O)
3450–3100(NH, NH2, OH),
1717–1655(C O)
3450–3100(NH, NH2, OH),
1717–1650(C O)
3400–3100(NH, NH2), 1717–1660(CO) (50.16) (4.06) (12.53) (4.78)
50.12 4.03 12.48 4.72
(46.57) (3.69) (12.07)
46.53 3.66 12.03
(52.46) (5.87) (12.75)
52.43 5.84 12.70
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
(5.76)
5.73
(5.61)
5.57
(5.48)
5.45
—
—
—
—
—
—
—
—
—
—
—
—
—
10a
10b
10c
11a
11b
11c
12a
12b
12c
13a
13b
13c
13d
14a
14b
14c
14d
15a
15b
15c
15d
50.93 5.67 12.35
(49.66) (5.38) (12.07)
49.62 5.35 12.03
(50.71) (3.76) (11.37)
50.68 3.72 11.34
(49.42) (3.67) (11.08)
49.38 3.64 11.03
(48.28) (3.43) (10.83)
48.23 3.38 10.79
(50.91) (3.94) (11.42) (5.23)
50.87 3.90 11.38 5.19
(49.61) (3.84) (11.13) (5.09)
49.58 3.81 11.90 5.04
(48.46) (3.60) (10.87) (4.98)
48.42 3.55 10.83 4.92
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
50.60 3.49 12.27
(52.36) (4.23) (14.09)
52.32 4.18 14.06
(51.78) (3.33) (10.06)
51.73 3.29 10.03
(51.78) (3.33) (10.06)
51.75 3.27 10.01
(48.39) (3.28) (10.84)
48.35 3.23 10.80
(49.98) (3.89) (12.49)
49.92 3.84 12.45
(51.96) (3.49) (10.10) (4.62)
51.93 3.45 9.98 4.58)
(51.96) (3.49) (10.10) (4.62)
51.91 3.43 9.96 4.55
(42.01) (2.98) (9.42) (4.31)
41.99 2.94 9.38 4.27
—
(5.10)
4.98
(5.10)
4.96
(5.49)
5.46
(5.27)
5.23
—
—
—
—
—
—
—
—

1172
N. A. A. El-Kanzi et al.
SCHEME 2
CH3 group, and NH2 group at δ 6.75. The mass spectrum showed the
molecular ion peak (M+, C18H17O3N4I) at m/z 464.
The activity of the carbonyl group in position 4 and the activity of
the methyl group at C2 rendered compound 9, which contained iodine to
react with different aromatic amine and different nitroso compounds to
give new Schiff bases 10a–c and 13a–d. The structures of these newly
synthesized Schiff bases compounds 10a–c and 13a–d were confirmed
by their elemental analysis, IR, 1H NMR, and mass spectra (cf. Tables I,

1173

1174

Thiazolidinone Derivatives
1175
II, III). The activity of the azamethine center in compounds 10a–c and
13a–d is more avaliable than the activity of the NH group toward the
addition process of chloroacetyl chloride, and this mentioned phenom-
ena is due to the presence of the π electron, which makes the foundation
of the δ positive and δ negative charge on the carbon and nitrogen atom,
respectively, more easy than the presence of this phenomena on the NH
group in which the bonding between nitrogen and hydrogen whether
strong according the nature of this bonding, which leads to decreased
mobility devise of the hydrogen atom of this NH group. Thus compound
10a–c reacted with chloroacetylchloride or mercaptoacetic acid9 to give
spiro β-Lactams and spiro thiazolidinone compounds 11a–c and 12a–
c. The structure of compounds 11a–c and 12a–c were confirmed by
1
their elemental analysis, IR, H NMR, and mass spectra (cf. Tables
I, II, III). Also we synthesized isolated β-lactams and thiazolidinone
compounds by the reaction of new Schiff bases 13a–d with chloroacetyl
chloride and/or mercaptoacetic acid to give 14a–d and 15a–d. The struc-
tures of these compounds were confirmed by their elemental analysis,
1
IR, H NMR, and mass spectra (cf. Tables I, II, III). We studied the
effect of iodine on the antimicrobial activity of the synthesized com-
pound. Thus the activity of eight synthesized compounds was examined
in vito against three groups of microorganisms, including six strains
of Gram positive bacteria, five strains of Gram negative bacteria, and
three strains of fungi. The compounds were divided into two groups,
four compounds with iodine in their structures and the other four com-
pounds without iodine.
Several organo compounds are well authenticated to have antimi-
crobial activity versus many species of bacteria and fungi.12−17 These
authors pointed out that some of these compounds are useful in the
treatment and/or control of human, animal, and plant diseases. The
present investigation was carried out to investigate the antimicrobial
activity of the eight synthesized compounds and shed new light on the
effect of iodine on the antimicrobial activity of the eight synthesized
compounds selected from the prepared compounds.
MATERIAL AND METHODS
Organisms
The microorganisms (No S. 1, 4, 6, 8, 9, 13, and 14) were obtained from
the culture collection of the United State Department of Agriculture,
Northern Regional Research Laboratory (Peoria, Illinois. USA), while
others were obtained from the Botany Department microorganism col-
lection and identified according to a key given in Bergy’s Manual of

1176
N. A. A. El-Kanzi et al.
TABLE IV Antimicrobial Potentialities of the Tested Compounds
Expressed as Size (mm) of the Inhibition Zone
Compound
Name
2
3a 4a 5a
9
10a
11a
12a Ampicillin Nystatin
1-Bacillus subtilis
NRS-744
+
+
+
+
++
++ + + + + + +
+
+
+
−
−
−
2-Micrococcus luteus ++ ++ + ++ ++ + + + + + + + + +
SW 712
3-Bacillus
++ ++ +
+
+ + + ++ + + + + + +
megaterium SW
354
4-Staphylococcus
aureus B-767
5-Streptomyces sp.
SW 123
6-Bacillus cereus
ATCC-9634
7-Serratia Mar SW
98
8-Pseudomonas
aeruginosa ATCC-
6NA10245
++
++
++
+
+
−
+
+
+
+
+
+
+
+ + + ++ + + + + + +
+
+
+
+
+
−
−
−
−
−
++
++
++ + + +
+ ++ ++
++ + + + + + +
−
−
+
+
++
+
+
++ + + +
++ + + +
−
++
9-Escherichia coli
B-3704
10-Salmonella sp.
SW 476
11-Pseudomonas sp.
SW 653
12-Sacharomyces
cerevisiae SW 201
13-Condida
−
+
−
+
+
+
+
+
+
+
−
+
+
−
+
+
+
+
+
−
+
+
+
++
++ + + +
+
+
+
−
−
−
−
−
+
+
++ + + + + + +
++ + + + + + +
++ + + + ++
++
++ + + + + + + ++
albicans
IMRU3669
14-Aspergillus
flouus S-C 43313
+
−
+
+
++
++ + + + + + +
−
+
Determinative Bacteriology.18 Sacharomyces cerevisiae were identified
as ascosporogenous.
Media
For the disc diffusion method, nutrient (NB) was used for cultivating the
bacteria. It contained (g/L) the following: beef extract, 3; peptone, 5; and
pH, 7.0. Czapek-Dox’s agar medium was used for cultivating the fungi.
It contained the following: (g/L) sucrose, 30.0; NaNO3, 2.0; KCl, 0.5;

Thiazolidinone Derivatives
1177
K2HPO4, 1.0; MgSO4, 7H2O, 0.5; FeSO4, 0.0004; agar, 20; and pH, 7.0–
7.2. malt extractagar was used for cultivating the yeast. It contained
the following: (g/L). malt extract, 20; peptone, 1; dextrose, 20; agar, 20;
and pH, 7.0–7.2.
Preparation of Bacterial Suspensions
Suspensions of the microorganisms were prepared by suspending each
bacteria in 5 mL sterile nutrient broth media, using a standard loop
and then incubating the inoculated nutrient broth at 37◦C for 2 h. One
mL of each suspension was added to the center of the sensitivity testing
plate. A sterile, dry cotton-wool swap was used to spread the inoculum
on the media. The inocula were allowed to dry for a few minutes.
Preparation of Discs
Five compounds were tested as 200 µg/mL (W/V) solutions in sterile
DMSO. Discs of 6-mm diameter of filter paper were placed in a petri
dish (each one contained 10 discs) and then sterilized in a hot air oven
at 180◦C for 1 h. After cooling, 11 mL of the chemical solution was added
onto each of the 10 discs to make a 20-µg concentration perone discs.
The discs were dried in the incubator at 35–37◦C, for 1 h, or dried over
phosphorous pentaoxide (P2O5) in a dissector under vacuum, and then
distributed on the inocula by sterile forceps.
Each disc should be pressed down on the medium and should not be
moved once in place. The plates were incubated at 37◦C overnight. The
diameters of the clear zones of inhibition were measured to the nearest
0.5 mm, compared to DMSO, under the same standardized conditions.
The data obtained are expressed as the size (mm) of inhibition zone. The
diameter of the inhibition zones were high: (+ + +) (20–16 mm), moder-
ate (++): (15–12 mm), slight (+): (11–1 mm), and no zone of inhibition
(negative) (−).
Disc Diffusion Method for Three Tested Fungi
For the disc diffusion,19 the discs of standard concentration (100 µg/disc)
of each of the five tested compounds were appropriately placed on the
surface of an agar plate freshly seeded with standard inoculum of young
culture (3 days old). The plates were kept at 5◦C for 1 h to allow diffusion
of the compounds through the agar media. The plates of the fungal
test organisms were maintained at 30◦C for 4 days. At the end of the
incubation period, the inhibition zones were measured.

1178
N. A. A. El-Kanzi et al.
Standard Antimicrobial and Antifungal
The preliminary antimicrobial20 was recorded in comparison to stan-
dard antibacterial ampicillin (10 mg/ml) and antifungal nystatin (10
mg/ml) in distiled water.
RESULTS AND DISCUSSION
Many antimicrobial agents have been introduced into therapy;21,22 how-
ever, the field still needs extensive efforts for the development of new
antimicrobial agents of superior activity and less toxic side effects as
well as to overcome the highly resistant strains of microorganisms. The
data of the disc susceptibility tests for the compounds containing iodine,
i.e., 9, 10a, 11a,12a, clearly showed significant and potent antimicro-
bial activity (bactericidal and fungicidal) against the all-tested Gram
positive bacteria and Gram negative bacteria and fungi. The compounds
did not contain iodine, i.e., 2, 3a, 4a, 5a revealed weak susceptibility for
the tested organisms compared with those of iodine, indicating that the
presence of iodine in the compounds’ structures enhanced the antimi-
crobial activity of the eight synthesized compounds. Compounds 11a
and 12a exhibited the highest antimicrobial activity and were capable
of inhibiting the growth of the all examined organisms.
EXPERIMENTAL SECTION
Melting points are uncorrected. IR spectra were measured as KBr pel-
lets on a pye-unicam sp 1,000 spectrophotometer. 1H NMR spectra were
recorded in (2H6) dimethylsulfoxide at 200 MHz on a Varian Gemini
NMR spectrometer using Mesi as an internal reference. Mass spectra
were obtained on a Shimadzu GCMS-QP 1000 EX mass spectrometer
at 70 eV. Elemental analysis were carried out at the Microanalytical
Center of Cairo University.
Synthesis of 2,4-Diamino 5,10-dioxo-1,5,10,11-
tetrahydrobenzo[g]quino-line-3-ethyl Carboxylate 1
A solution of the appropriate ethylcyano acetate and urea (0.01 mole),
which was prepared in situ in ethanol (30 mL) containing (0.5 mL)
piperidine, was treated with 1,4-naphthoquinone (0.02 mole, 1.58 g).
The reaction mixture was heated under reflux for 10–12 h. The solvent
was then evaporated under reduced pressure. Poured onto ice water
acidified by HCl, the solid product that formed was collected by filtration
and crystallized from DMF.

Thiazolidinone Derivatives
1179
Synthesis of Compound 2
A stream of dry hydrogen chloride gas was passed through a mixture of
compound 1 (3.13 gm, 10 mmol) and an appropriate acetonitrile (0.41
gm, 10 mmol) in dioxane (30 mL) for about 12 h. The reaction mixture
was heated on a water bath for 2 h after passing hydrogen chloride gas.
The reaction mixture was diluted with ice water and basified with 10%
aq. ammonium hydroxide. The solid obtained as washed with water,
dried, and crystallized from dimethyl formamide.
Synthesis of New Schiff Bases 3a–c and 6a–d
A solution of 2 (0.01 mole, 3.08 gm) in DMF (30 mL) was treated with dif-
ferent aromatic amines (0.01 mole) and/or different nitroso compounds
(0.0l mole) in the presence of a catalytic amount of piperidine (0.5 mL).
The reaction mixture was heated under reflux for 8–9 h (monitored by
TLC). The solvent was then evaporated under reduced pressure, and
the residue was treated with ice water acidified by HCl. The solid prod-
uct was collected and crystallized from the proper solvent (cf. Table I).
Synthesis of Spiro β-Lactam 4a–c and Thiazolidinone 5a–c
A solution of 3a–c (0.01 mole) in DMF (20 mL) was treated with
chloroacetyl chloride or mercaptoacetic acid (0.01 mole) in the presence
of (0.5 ml) triethylamine catalyst. The reaction mixture was heated un-
der reflux for 15–17 h (monitored by TLC). The solvent was then evap-
orated under reduced pressure, and the residue was treated with ice
water. The solid product was collected and crystallized from the proper
solvent (cf. Table I).
Synthesis of Isolated β-Lactam 7a–d and Thiazolidinone 8a–d
A solution of 6a–d (0.01 mole) in DMF (30 mL) was treated with
chloroacetyl chloride or mercaptoacetic acid (0.01 mole), which was
added drop by drop and stirred for 1 h in the presence of triethyl amine
catalyst. The reaction mixture was heated under reflux for 18–20 h
(monitored by TLC). The solvent was then evaporated under reduced
pressure, and the residue was treated with ice water. The solid product
was collected by filtration and crystallized from the proper solvent (cf.
Table I).
Synthesis of Compound 9
A solution of ethyl Iodide (0.01 mole, 1.56 gm) was treated to compound
2 (0.01 mole, 3.08 gm) drop by drop and heated together by fussion for

1180
N. A. A. El-Kanzi et al.
1 h; the solid product was collected by ethanol and crystallized from the
proper solvent (cf. Table I).
Synthesis of New Schiff Bases 10a–c and 13a–d
A solution of 9 (0.01 mole, 4.64 gm) in DMF (10 mL) and ethanol (20 mL)
was treated with different aromatic amine (0.01 mole) and/or different
nitroso compounds (0.01 mole) in the presence of a catalytic amount
of piperidine (0.5 ml). The reaction mixture was heated under reflux
for 7–8 h (monitored by TLC). The solvent was then evaporated under
reduced pressure, and the residue was treated with ice water acidified
by HCl. The solid product was collected by filtration and crystallized
from the proper solvent (cf. Table I).
Synthesis of Spiro β-Lactam 11a–c and Thiazolidinone 12a–c
A solution of 10a–c (0.01 mole) in DMF (30 mL) was treated with
chloroacetyl chloride or mercaptoacetic acid (0.01 mole) in the presence
of (0.5 ml) triethylamine catalyst. The reaction mixture was heated un-
der reflux for 16–18 h (monitored by TLC). The solvent was then evap-
orated under reduced pressure, and the residue treated with ice water.
The solid product was collected by filtration and crystallized from the
proper solvent (cf. Table I).
Synthesis of Isolated β-Lactam 14a–d and Thiazolidinone
15a–d
A solution of 13a–d (0.01 mole) in DMF (30 mL) was treated with
chloroacetyl chloride or mercaptoacetic acid (0.01 mole), which was
added drop by drop and stirred for 1 h in the presence of triethylamine
catalyst. The reaction mixture was heated under reflux for 19–20 h
(monitroed by TLC). The solvent was then evaporated under reduced
pressure, and the residue was treated with ice water. The solid product
was collected by filtration and crystallized from the proper solvent (cf.
Table I).
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Thiazolidinone Derivatives
1181
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