Synthesis of new phenolic compounds and biological evaluation as antiproliferative agents

Article abstract of DOI:10.1177/1747519819895238

New series of phenolic azomethine compounds in addition to 5-arylidene thiazolidinones are synthesized and screened for their anticancer activity against the brain cancer cell line SNB-75 and non-small lung cancer cells HOP-92. The azomethine derivative 12b is the most active compound against SNB-75 displaying an IC₅₀ value of 0.14 μM. Compounds 7b, 16a and 27d display submicromolar activity against the HOP-92 cell line with IC₅₀ values of 0.73, 0.74 and 0.81 μM, respectively. Moreover, studying the cytotoxic effects of the most active compounds against normal lung cells WI-38 revealed that compounds 7b, 16a and 27d showed high safety profiles as anticancer agents.

Full text of DOI:10.1177/1747519819895238

895238CHL0010.1177/1747519819895238Journal of Chemical ResearchIbrahim et al.
research-article2019
Research Paper
Journal of Chemical Research
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Synthesis of new phenolic compounds and
biological evaluation as antiproliferative agents
https://doi.org/10.1177/1747519819895238
DOI: 10.1177/1747519819895238
journals.sagepub.com/home/chl
Marwa A Ibrahim , Riham F George, Sahar M Abou-Seri
and Samir M El-Moghazy
Abstract
New series of phenolic azomethine compounds in addition to 5-arylidene thiazolidinones are synthesized and screened
for their anticancer activity against the brain cancer cell line SNB-75 and non-small lung cancer cells HOP-92. The
azomethine derivative 12b is the most active compound against SNB-75 displaying an IC50 value of 0.14μM. Compounds
7b, 16a and 27d display submicromolar activity against the HOP-92 cell line with IC50 values of 0.73, 0.74 and 0.81μM,
respectively. Moreover, studying the cytotoxic effects of the most active compounds against normal lung cells WI-38
revealed that compounds 7b, 16a and 27d showed high safety profiles as anticancer agents.
Keywords
anticancer, azomethines, phenolic compounds, synthesis, thiazolidinones
Date received: 19 August 2019; accepted: 20 November 2019
effects.4 Luo and co-workers reported the synthesis of salic-
ylaldehyde-o-phenylenediamine Schiff base I, which dis-
played antitumor activity against the leukaemia cell lines
Introduction
Cancer is one of the most feared diseases worldwide affect-
ing around 14 million people every year.1 Specifically, lung
cancer is a major cause of death with a survival rate of only
about 18%.2 Although, chemotherapy remains one of the
most effective strategies among all cancer treatments, resist-
ance to chemotherapeutic agents is the major challenge.3
Thus, the discovery of new antitumor agents with promising
K562 and HEL with IC50 values of 11.95 and 9.75μM,
respectively (Figure 1).5Moreover, the phenolic azomethine
derivatives II and III exhibited good anticancer activity
against the colon cancer cell line HCT-116.6,7
biological activity and safety profiles remains a necessity
for scientific research.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo
University, Cairo, Egypt
In addition, it is well established that phenolic azomethine
derivatives display biological activity as anticancer, antibac-
terial and anti-inflammatory agents.4,5 In this context, many
phenolic azomethine–based molecules featured with differ-
Corresponding author:
Marwa A Ibrahim, Department of Pharmaceutical Chemistry, Faculty of
Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box 11562,
Cairo, Egypt.
ent aryl/heteroaryl moieties were reported to exert antitumor Email: marwa.abdelaziz@pharma.cu.edu.eg

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Journal of Chemical Research 00(0)
Figure 1. Structures of some reported anticancer compounds bearing phenolic/2-hydroxy-1-naphthyl azomethines, and the design
of the proposed target compounds.
Furthermore, there is evidence that azomethine deriva- target compounds. Therefore, two series with the phenolic
tives obtained from the condensation of 2-hydroxy- azomethine moiety (scaffold A), namely, 2-hydroxy-
1-naphthaldehyde (fused phenolic azomethines) showed 1-phenylazomethines 3a, 7a,c, 12a, 16a, 20a and 24a and
promising antitumor activity.8,9 In 2018, 1-[(4-fluoroben- 2-hydroxy-1-naphthyl-azomethines 3b, 7b,d, 12b, 16b,
zylimino)methyl]naphthalene-2-ol (IV) was described by 20b and 24b, were designed to compare the lipophilic
Devi et al.8 to exert antiproliferative activity against the effect on the obtained antiproliferative activity (Figure 1).
alveolar adenocarcinoma A459, breast cancer MCF7 and The phenolic azomethine moiety was extended by a phe-
prostate cancer DU145 cell lines (Figure 1). Moreover, nyl core linked to a pendent aryl group (either phenyl
cytotoxic studies showed that the phenolic azomethine 3a,b, 7a–d, 16a,b, 20a,b and 24a,b or 4,6-dimethylpy-
derivative V elicited promising cytotoxic activity against rimidine (12a,b)) through different linkers to ensure vari-
five cell lines: HepG2, MGC80-3, T-24, SK-OV-3 and able degrees of flexibility between the phenyl core and the
HL-7702.9 Lara and co-workers10 discovered the imino- side chain.
methyl-2-hydroxy-1-naphthaldehyde derivative salermide
Literature reviews showed that compounds containing a
VI that displayed anticancer activity against the leukaemia thiazole core, for example, compound VII, or a thiazolidi-
cell lines MOLT4 and KG1A.
none core, for example, compound VIII, displayed potent
Based on the aforementioned findings, the phenolic antitumor activity against several cell lines (Figure 1).11,12
azomethine moiety was selected to build up the final Consequently, a new approach was adopted through

Ibrahim et al.
3
bioisosteric replacement of the azaphenyl core in 7a–d with thereportedprocedures, 3-aminobenzoicacid1wasemployed
a thiazolidinone ring (scaffold B) as in compounds 27a,b,d,e. as a suitable precursor for the synthesis of the intermediate
Finally, the phenolic moiety in the latter congeners was azomethines 2a,b.13,14 The amide derivatives 3a,b were pre-
replaced by a 2-thienyl ring in 27c,f to prove the importance pared by reacting the 3-aminobenzoic acid derivatives 2a,b
of the phenolic moiety on the cytotoxic activity.
with carbonyldiimidazole (CDI) in dry dichloromethane/
The cytotoxic activity of all the target compounds was dimethylformamide (DMF) at 0°C followed by reaction with
tested against the lung cancer cell line HOP-92 and the brain benzylamine at room temperature (Scheme 1).
cancer cell line SNB-75. Subsequently, the growth inhibitory
Starting from 3-nitroaniline (4), derivatives 6a,b were
activity of the most active compounds against the human synthesized adopting methods described in the previous
normal lung fibroblast cell line WI-38 was tested.
literature.15,16 Synthesis of the required Schiff bases 7a–d
was performed via reaction of the aryl amino intermediates
6a,b with the appropriate aldehyde in refluxing ethanol in
the presence of a catalytic amount of glacial acetic acid
(Scheme 2). Meanwhile, intermediate 10 was synthesized
by heating the 2-mercapto-4,6-dimethylpyrimidine hydro-
chloride (9) in ethanol in the presence of potassium car-
bonate to liberate the free base, followed by the addition of
chloro-acylated compound 8. Reduction of the nitro deriv-
ative 10 using SnCl2/HCl afforded the corresponding
amino counterpart 11, which in turn reacted with the
appropriate aldehyde to yield the desired Schiff bases
12a,b (Scheme 2).
Results and discussion
Chemistry
The target compounds bearing a phenyl core 3a,b, 7a–d,
12a,b, 16a,b, 20a,b and 24a,b were synthesized adopting the
chemical pathways outlined in Schemes 1–5. According to
Moreover, derivatives 14 and 15 were synthesized from
3-nitroacetophenone (13) according to the reported meth-
ods.16,17 The target azomethine derivatives 16a,b were pre-
pared via the reaction of the aryl amino intermediate 15 as
mentioned previously (Scheme 3).
To afford the 3-nitrobenzenesulfonamide derivative 18,
3-nitrobenzenesulfonyl chloride (17) was treated with ben-
zylamine, followed by reduction with SnCl2/HCl to yield
the corresponding amino derivative 19. The target final
Scheme 1. Synthetic pathway to compounds 3a,b. Reagents
and conditions: (a) aldehyde, EtOH, glacial CH3COOH, 70°C,
6h, yield 77%–85%; (b) CDI, benzylamine, CH2Cl2/DMF, RT,
24h, yield 52%–76%.
Scheme 2. Synthetic pathway to compounds 7a–d and 12a,b. Reagents and conditions: (a) benzoyl chloride/phenylacetyl chloride,
Et3N, CH2Cl2, reflux, 5h, yield 69%–86%; (b) SnCl2·2H2O, conc. HCl, absolute EtOH, RT, 48h, yield 45%–80%; (c) appropriate
aldehyde, glacial CH3COOH, absolute EtOH, 70°C, 6h, yield 65%–86%; (d) ClCH2COCl, CH2Cl2, reflux, 5h, yield 88%; and (e)
anhydrous K2CO3, absolute EtOH, reflux, 6h, yield 74%.

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Journal of Chemical Research 00(0)
Scheme 3. Synthetic pathway to compounds 16a,b. Reagents and conditions: (a) benzaldehyde, NaOH, EtOH, RT, 2h, yield 92%;
(b) SnCl2·2H2O, conc. HCl, absolute EtOH, reflux, 4h, yield 56%; and (c) appropriate aldehyde, absolute EtOH, glacial CH3COOH,
70°C, 12–15h, yield 74%–79%.
Scheme 4. Synthetic pathway to compounds 20a,b. Reagents and conditions: (a) benzylamine, triethylamine, CH2Cl2, RT, 2h,
yield 77%; (b) SnCl2·2H2O, absolute EtOH, RT, overnight, yield 58%; and (c) appropriate aldehyde, glacial CH3COOH,
absolute EtOH, 70°C, 5h, yield 81%–87%.
Scheme 5. Synthetic pathway to compounds 24a,b. Reagents and conditions: (a) PhNCO, CH2Cl2, Et3N, RT, 4h, yield 92%;
(b) (COCl)2/CH2(COCl)2, dioxane, RT, 48h, yield 79%–83%; (c) SnCl2·2H2O, HCl, EtOH, reflux, 2h, yield 20%–25%; and
(d) appropriate aldehyde, absolute EtOH, glacial CH3COOH, 70°C, 4h, yield 58%–65%.
compounds 20a,b were prepared by reacting compound 19 13C NMR spectra of compounds 24a,b showed signals at
with the corresponding aldehydes in refluxing ethanol 159.2–160.7 and 163.8–171.1 corresponding to the C=N
(Scheme 4).
and C=O carbons, respectively, in addition to aromatic sig-
In attempts to prepare new compounds with a rigidified nals confirming their carbon skeletons.
linker between the phenyl core and the side chain, the inter-
The target compounds bearing a thiazolidinone core 27a–f
mediate imidazolidine-trione derivative 22a and pyrimi- were synthesized according to the pathway depicted in
dine-trione derivative 22b were prepared through the Scheme 6. According to the reported procedure, 2-amino-
reaction of N,N′-disubstituted urea derivative 21 with oxa- thiazolidin-4-one (25) was prepared by reacting thiourea with
lyl chloride or malonyl chloride in dioxane (Scheme 5). ethyl chloroacetate.18 Reaction of the precursor 25 with ben-
Upon reduction of the nitro group in intermediates 22a,b zoyl chloride or phenylacetyl chloride afforded the intermedi-
with SnCl2/HCl, reductive cleavage of the heterocyclic ates 26a,b. Condensation of compounds 26a,b with different
rings occurs affording the urea derivative 23. The 1H NMR aldehydes gave the target analogues 27a–f. The structures of
spectrum of 23 revealed the presence of three exchangeable the target compounds were confirmed by elemental analysis
protons at 5.11, 8.36 and 8.54ppm correlating with the pro- and spectral data. 1H NMR and 13C NMR spectra of some of
tons of the primary aromatic amine and protons of the sec- the final compounds are given as supplementary materials.
ondary amino groups of urea, respectively, confirming
reductive cleavage of the heterocyclic ring of the interme-
diates 22a,b. Moreover, reduction of the nitro derivatives Biological evaluation
22a,b with Fe/NH4Cl or Fe/acetic acid did not afford the
In vitro cytotoxic activity against SNB-75
target amino derivatives. The final compounds 24a,b were
and HOP-92 cell lines
obtained by the reaction of the amino derivative 23 with the
1
appropriate aldehyde. The H NMR spectra of the ana- The prepared compounds 3a,b, 7a–d, 12a,b, 16a,b, 20a,b,
logues 24a,b showed the presence of two singlets at 8.94, 24a,b and 27a–f were assayed in vitro for their cytotoxicity
9.66 and 13.08, 15.66ppm corresponding to the azome- utilizing the MTT assay against the brain cancer cell line SNB-
thine protons and OH protons, respectively. Moreover, the 75 and the non-small lung cancer cell line HOP-92 using

Ibrahim et al.
5
Scheme 6. Synthetic pathway to compounds 27a–f. Reagents and conditions: (a) appropriate acid chloride, pyridine, reflux, 4h,
yield 60%–78%; (b) appropriate aldehyde, absolute EtOH, CH3COONa, reflux, 4h, yield 62%–85%.
sorafenib as a positive control. The synthesized compounds 2-hydroxynaphthyl moiety in 12b with a 2-hydroxyphenyl
can be classified into derivatives with a phenyl core 3a,b, 7a– moiety as in the congener 12a (IC50 =25.46μM) was detri-
d, 12a,b, 16a,b, 20a,b and 24a,b and derivatives with a thia- mental to the antiproliferative activity.
zolidinone core 27a–f. As shown in Table 1, almost all the
Concerning the thiazolidinone derivatives 27a–f, com-
synthesized compounds exhibited mild to moderate cytotoxic pounds with an acetamide linker between the thiazolidi-
activities against both cell lines. Moreover, compound 12b none ring and the pendent phenyl ring, that is, 27d–f,
displayed submicromolar activity against the brain cancer cell displayed comparable cytotoxic activity to the correspond-
line SNB-92. On the other hand, derivatives 7b, 16a and 27d ing analogues with an amide linker (27a–c). The 2-hydroxy-
displayed submicromolar activity against the non-small lung phenyl derivatives 27a,d displayed the highest anticancer
cancer cell line HOP-92.
activity with IC50 values of 1.59 and 1.39μM. Replacing
Regarding the brain cancer cell line SNB-75, deriva- the 2-hydroxyphenyl moiety in 27a,d with a 2-thienyl moi-
tives with a phenyl core, 3a,b, 7a–d, 12a,b, 16a,b, 20a,b ety as in compounds 27c,f decreased the antiproliferative
and 24a,b, displayed a wide range of anticancer activity activity, which highlights the impact of the 2-hydroxyphe-
with IC50 values ranging from 0.14 to >20μM. Compounds nyl moiety on the anticancer activity.
3a, 7a,b, 12b, 20a, 24b, 27a,d and 27e (IC50 range=0.14–
With regard to the non-small lung cancer cell line HOP-
3.25μM) presented higher antiproliferative activity than 92, compounds with a phenyl core, 3a,b, 7a–d, 12a,b,
the positive control sorafenib (IC50 =14.86μM). In partic- 16a,b, 20a,b and 24a,b, displayed a wide range of antican-
ular, compound 12b showed superior potency with an IC50 cer activity with IC50 values ranging from 0.73 to 16.49μM.
value of 0.14μM. With respect to the effect of the substitu- Compounds 3a, 7a,b, 16a and 27d (IC50 =0.74–1.62μM)
tion pattern on the derivatives with a phenyl core, com- presented higher anticancer activity than the positive con-
pounds 3a,b, 7a–d, 12a,b, 16a,b, 20a,b and 24a,b, and the trol sorafenib (IC50 =6.87μM). In contrast with the SNB-75
2-hydroxyphenyl derivatives 3a, 7a, 7c, 16a and 20a cancer cell line, the 2-hydroxynaphthyl derivatives 7b, 7d,
exhibited higher anticancer activity than the corresponding 12b, 20b and 24b showed higher antiproliferative activity
2-hydroxynaphthyl derivatives 3b, 7b, 7d, 16b and 20b, than the corresponding 2-hydroxyphenyl derivatives 7a,
except for derivatives bearing ureido linker 24a,b and 7c, 12a, 20a and 24a, with the exception of compounds
compounds featuring a mercaptodimethylpyrimidine side bearing the reversed amide linkage (3a,b) and an α,β-
chain 12a,b.
unsaturated ketone linkage (16a,b).
Dealing with the linker length, compounds 7a,b with an
Studying the effect of the spacer, derivatives 7a,b with
amide linker showed good anticancer activity with IC50 val- an amide linker between the phenyl core and the pendent
ues of 1.56 and 2.27μM, respectively. Increasing the spacer phenyl showed good anticancer activity with IC50 values of
length by attaching a benzyl group to the amide linkage as in 1.08 and 0.73μM, respectively. Increasing the spacer length
7c,d decreased the activity more than four times. Meanwhile, by attaching a benzyl group to the amide linkage (7c,d)
replacing the amide linkage in the derivatives 7c,d with a decreased the antiproliferative activity by six- and fourfold,
reversed amide linkage 3a,b or sulfamoyl linkage 20a,b respectively. Meanwhile, replacing the acetamide linkage
resulted in compounds with comparable antiproliferative in the analogues 7c,d with a reversed acetamide linkage as
activity. Replacing the acetamide linkage in the derivatives in 3a,b or an α,β-unsaturated ketone linkage as in 16a,b
7c,d with a ureido linkage as in 24a,b increased the antican- resulted in an increase in the antiproliferative activity of the
cer effect of the 2-hydroxynaphthyl derivative. Conversely, 2-hydroxyphenyl derivatives; whereas, replacing the aceta-
an α,β-unsaturated ketone linkage as in 16a,b resulted in a mide linkage in the derivatives 7c,d with a urea linkage
sharp decrease in the antiproliferative activity of the (24a,b), a sulfamoyl linkage (20a,b) or increasing the
2-hydroxynaphthyl derivative 16b.
linker length as in the mercaptodimethylpyrimidine deriva-
Furthermore, the mercaptodimethylpyrimidine deriva- tives (12a,b) did not have a marked effect on the anticancer
tive 12b with the longest linker displayed superior antican- activity of the corresponding derivatives.
cer activity against the SNB-92 cancer cell line with
Concerning the compounds with a thiazolidinone core
IC50 =0.14μM. On the other hand, replacing the 27a–f, they displayed a wide range of anticancer activity

6
Journal of Chemical Research 00(0)
Table 1. Cytotoxic activity of the synthesized compounds (IC50, μM) against the brain cancer cell line SNB-75 and the non-small
lung cancer cell line HOP-92.
Compound
Ar
n
IC50 (μM)
SNB-75
HOP-92
3a
3b
7a
7b
7c
7d
12a
12b
16a
16b
20a
20b
24a
24b
27a
27b
27c
27d
27e
27f
2-HO-C6H4
2-HO-C10H6
2-HO-C6H4
2-HO-C10H6
2-HO-C6H4
2-HO-C10H6
2-HO-C6H4
2-HO-C10H6
2-HO-C6H4
2-HO-C10H6
2-HO-C6H4
2-HO-C10H6
2-HO-C6H4
2-HO-C10H6
2-HO-C6H4
2-HO-C10H6
2-Thienyl
0
0
0
0
1
1
0
0
0
0
0
0
0
0
0
0
0
1
1
1
2.86±0.12
8.90±0.38
1.56±0.07
2.27±0.13
7.09±0.33
13.71±0.82
25.46±1.71
0.14±0.02
4.89±0.25
47.64±2.81
3.25±0.22
8.55±0.61
4.73±0.25
3.15±0.15
1.59±0.07
5.30±0.19
8.02±0.36
1.39±0.07
2.32±0.09
8.98±0.25
14.86±0.43
1.62±0.03
5.11±0.17
1.08±0.09
0.73±0.04
6.66±0.33
2.91±0.12
8.54±0.39
5.69±0.21
0.74±0.04
1.97±0.07
16.49±0.95
3.45±0.08
11.35±0.05
3.98±0.12
3.26±0.19
6.38±0.36
9.36±0.47
0.81±0.07
6.38±0.25
14.31±0.81
6.87±0.41
2-HO-C6H4
2-HO-C10H6
2-Thienyl
Sorafenib
with IC50 values ranging from 0.81 to 14.31μM. The their potential safety towards normal cells. The results in
2-hydroxyphenyl derivatives 27a,d displayed the highest Table 2 showed that the tested compounds 7b, 12b, 16a and
anticancer activity with IC50 =3.26 and 0.81μM, whereas 27d exhibited non-significant cytotoxic impact towards the
the thienyl analogues 27c,f exhibited the lowest antiprolif- normal cell line WI-38. In addition, the derivatives 7b, 16a
erative activity (IC50 =9.36 and 14.31μM). As for the influ- and 27d displayed good selectivity indices, thereby provid-
ence of the linker length, replacing the amide linker in ing good safety as anticancer agents.
compounds 27a–c by an acetamide linker as in 27d–f
afforded congeners with comparable activity except for the
2-hydroxyphenyl derivative 27d which showed enhanced
Conclusion
cytotoxicity (IC50 =0.81μM).
In the present work, new series of 2-hydroxy-1-phenyl/2-
hydroxy-1-naphthyl azomethine compounds 3a,b, 7a–d,
12a,b, 16a,b, 20a,b and 24a,b in addition to 5-arylidene thia-
zolidinones 27a–f were synthesized and screened for their
anticancer activity against the brain cancer cell line SNB-75
In vitro cytotoxic activity towards non-
tumorigenic humanWI-38 cells
The cytotoxic effects of the most active compounds 7b, and the non-small lung cancer cell line HOP-92. The target
12b, 16a and 27d were examined against the non-tumori- compounds 7b, 12b, 16a and 27d displayed submicromolar
genic human lung fibroblast cell line WI-38 to investigate activity against both cell lines. Moreover, studying the

Ibrahim et al.
7
46–48°C, yield 0.34g (52%). IR ν (cm−1): 3396 (OH),
3059–3029 (CH aromatic), 2922 (CH aliphatic), 1631
(C=O), 1582 (C=N), 1496–1456 (C=C). 1H NMR
(DMSO-d6, 400MHz): δ 4.82 (s, 2H, CH2), 6.88–6.94 (m,
3H, aromatic H), 7.28–7.40 (m, 9H, aromatic H and NH),
7.48 (d, J=7.56Hz, 2H, aromatic H), 8.72 (s, 1H, CH=N),
13.46 (br s, 1H, OH, D2O exchangeable). 13C NMR
(DMSO-d6, 100MHz): δ 62.4 (CH2), 116.9, 119.1, 119.2,
127.7, 128.3, 129.1, 132.2, 132.9, 139.1 (aromatic car-
bons), 161.0 (C=N), 167.0 (C=O). Anal. calcd for
C21H18N2O2 (330.39): C, 76.34; H, 5.49; N, 8.48; found: C,
76.01; H, 5.63; N, 8.67%.
N-Benzyl-3-{[(2-hydroxynaphthalen-1-yl)methylidene]
amino}benzamide (3b): The title compound was separated
as yellow crystals and purified by preparative TLC using
chloroform as the mobile phase, m.p. 73–75°C, yield 0.58g
(76%). IR ν (cm−1): 3398 (OH), 3290 (NH), 3059–3034
(CH aromatic), 2922 (CH aliphatic), 1632 (C=O), 1614
(C=N), 1595–1541 (C=C). 1H NMR (DMSO-d6, 400MHz):
δ 4.89 (d, J=3.6Hz, 2H, CH2), 6.77 (d, J=9.32Hz, 1H, aro-
matic H), 7.22 (t, J=7.56Hz, 1H, aromatic H), 7.32 (t,
J=6.60Hz, 1H, aromatic H), 7.38–7.48 (m, 10H, aromatic
H and NH), 7.66 (d, J=7.72Hz, 1H, aromatic H), 7.75 (d,
J=9.32Hz, 1H, aromatic H), 8.14 (d, J=8.36Hz, 1H, aro-
matic H), 9.32 (s, 1H, CH=N), 14.42 (br s, 1H, OH, D2O
exchangeable). 13C NMR (DMSO-d6, 100MHz): δ 55.4
(CH2), 106.6, 119.1, 122.8, 125.5, 125.9, 128.2, 128.1,
128.4, 129.2, 129.4, 134.6, 137.6, 138.3 (aromatic carbons),
160.0 (C=N), 176.9 (C=O). MS (EI): m/z (%)=380 (M+,
0.01), 91 (100). Anal. calcd for C25H20N2O2 (380.45): C,
78.93; H, 5.30; N, 7.36; found: C, 78.70; H, 5.41; N, 7.64%.
Table 2. Cytotoxic activity of the most active compounds
against normal WI-38 cells and their selectivity indices.
Compound
IC50 (μM)
Selectivity
index
WI-38
HOP-92
7b
30.82±1.72
21.88±1.61
29.90±2.04
24.55±1.38
0.73±0.04
5.69±0.21
0.74±0.04
0.81±0.07
42
4
40
30
12b
16a
23d
cytotoxic effects of the most active compounds 7b, 16a and
27d against normal lung cells WI-38 showed good selectivity
indices ranging from 30 to 42; thus, these compounds provide
high safety profiles as anticancer agents.
Materials and methods
Chemistry
Starting materials and solvents were purchased from com-
mercial suppliers and were used without further purifica-
tion.MeltingpointsweredeterminedusinganElectrothermal
Stuart SMP3 digital melting point apparatus and are uncor-
rected. Elemental microanalyses were performed at the
Regional Centre for Mycology and Biotechnology,Al-Azhar
University. The infrared (IR) spectra were recorded on a
Shimadzu FTIR 8400S, Faculty of Pharmacy, Cairo
University. The proton nuclear magnetic resonance 1H NMR
spectra were performed in CDCl3 or DMSO-d6 using a
Bruker, 400MHz NMR spectrometer, Microanalytical Unit,
Faculty of Pharmacy, Cairo University. 13C NMR spectra
were recorded using a Bruker, 100MHz NMR spectrometer,
MicroanalyticalUnit,FacultyofPharmacy,CairoUniversity.
Mass spectra were obtained using a Finnigan SSQ 7000 GC/
MS, at the Micro Analytical Centre, Faculty of Science,
Cairo University. Reactions were followed by thin-layer
chromatography (TLC), using silica gel TLC plates with a
fluorescence indicator (F254) obtained from Merck and the
spots were visualized using a Vilber Lourmat ultraviolet
lamp at λͅ=254nm. The purity of the newly synthesized
compounds was assessed by TLC. Compounds 2a,19 2b,14
5a,20 5b,21 6a,16 6b,21 8,22 9,23 14,24 15,16 18,25 19,25 21,26
2518 and 26a27 were prepared according to the reported
procedures.
General procedure for the preparation
of the Schiff bases 7a–d, 12a,b, 16a,b,
20a,b and 24a,b
A solution of the appropriate amine 6a,b, 11, 15, 19, 23
(2.35mmol) in absolute ethanol (20mL) and salicylalde-
hyde (0.28mL, 2.59mmol) or 2-hydroxy-1-naphthalde-
hyde (0.41g, 2.35mmol) was heated under reflux for 4–15h
at 70°C in the presence of a catalytic amount of glacial ace-
tic acid. The reaction mixture was left to cool, the precipi-
tated crystals were filtered and recrystallized from an
appropriate solvent(s).
N-(3-((2-Hydroxybenzylidene)amino)phenyl)benzamide
(7a): The title compound separated as yellow crystals,
recrystallized from n-butanol, m.p. 175–177°C, yield 0.61g
(83%). IR ν (cm−1): 3445 (OH), 3308 (NH), 3055–3032
General procedure for the preparation of
compounds 3a,b
(CH aromatic), 1647 (C=O), 1620 (C=N), 1595–1558
1
A solution of the appropriate 3-aminobenzoic acid derivative (C=C). H NMR (DMSO-d6, 400MHz): δ 6.98–7.01 (m,
2a,b (2mmol) in dry dichloromethane containing 5%–20% 2H, aromatic H), 7.19 (d, J=7.96Hz, 1H, aromatic H),
volume DMF was cooled to 0°C in an ice bath. CDI (0.49g, 7.42–7.47 (m, 2H, aromatic H), 7.54–7.62 (m, 3H, aromatic
3mmol) was added, and the mixture was stirred for 1h. Next, H), 7.69–7.74 (m, 2H, aromatic H), 7.88 (s, 1H, aromatic
benzylamine (0.65mL, 6mmol) was added, and the mixture H), 7.99 (d, J=7.36Hz, 2H, aromatic H), 8.98 (s, 1H,
was stirred at room temperature for 24h. The reaction mix- CH=N), 10.38 (br s, 1H, NH, D2O exchangeable), 13.06 (br
ture was diluted with dichloromethane and washed with s, 1H, OH, D2O exchangeable). 13C NMR (DMSO-d6,
1M HCl and brine, dried over anhydrous sodium sulfate, fil- 100MHz): δ 114.1, 116.6, 117.1, 119.3, 119.70, 119.74,
tered and concentrated under reduced pressure.
128.1, 128.9, 130.1, 132.2, 133.0, 133.9, 135.2, 140.7,
N-Benzyl-3-[(2-hydroxybenzylidene)amino]benzamide 148.9, 160.8 (aromatic carbons), 163.8 (C=N), 166.2
(3a): The product was separated as yellow crystals, m.p. (C=O). MS (EI): m/z (%)=316 (M+, 54.45), 105 (100).

8
Journal of Chemical Research 00(0)
Anal. calcd for C20H16N2O2 (316.36): C, 75.93; H, 5.10; N,
8.86; found: C, 76.14; H, 5.23; N, 9.15%.
2-((4,6-Dimethylpyrimidin-2-yl)thio)-N-(3-((2-hydroxy-
benzylidene)amino)phenyl) acetamide (12a): The title
N-(3-(((2-Hydroxynaphthalen-1-yl)methylene)amino) compound separated as yellow crystals, crystallized from
phenyl)benzamide (7b): The product separated as yellow methanol, m.p. 139–140°C, yield 0.60g (65%). IR ν (cm−1):
crystals, recrystallized from n-butanol, m.p. 221–223°C, 3479 (OH), 3263 (NH), 3082 (CH aromatic), 2970 (CH ali-
yield 0.74g (86%). IR ν (cm−1): 3460 (OH), 3323 (NH), phatic), 1666 (C=O), 1605 (C=N), 1577–1543 (C=C). H
1
1
1653 (C=O), 1622 (C=N), 1593–1531 (C=C). H NMR NMR (DMSO-d6, 400MHz): δ 2.34 (s, 6H, 2 CH3), 4.07 (s,
(DMSO-d6, 400MHz): δ 7.03 (d, J=9.20Hz, 1H, aro- 2H, CH2), 6.96–7.00 (m, 3H, aromatic H), 7.13 (d,
matic H), 7.37 (t, J=8.16Hz, 1H, aromatic H), 7.49–7.63 J=7.72Hz, 1H, aromatic H), 7.38–7.47 (m, 3H, aromatic
(m, 6H, aromatic H), 7.76 (br s, 1H, aromatic H), 7.81 (d, H), 7.67–7.70 (m, 2H, aromatic H), 8.92 (s, 1H, CH=N),
J=7.92Hz, 1H, aromatic H), 7.94 (d, J=9.16Hz, 1H, aro- 10.39 (br s, 1H, NH, D2O exchangeable), 13.00 (br s, 1H,
matic H), 7.96 (s, 1H, aromatic H), 8.01 (d, J=7.48Hz, OH, D2O exchangeable). 13C NMR (DMSO-d6, 100MHz):
2H, aromatic H), 8.48 (d, J=8.44Hz, 1H, aromatic H), δ 23.8 (2 CH3), 36.0 (CH2), 112.9, 116.2, 116.5, 117.1,
9.66 (s, 1H, CH=N), 10.40 (br s, 1H, NH, D2O exchange- 118.0, 119.6, 119.7, 130.3, 133.0, 133.8, 140.5, 149.0,
able), 15.78 (br s, 1H, OH, D2O exchangeable). 13C NMR 160.7, 163.8, 167.3, 167.4 (aromatic carbons), 169.7
(DMSO-d6, 100MHz): δ 108.9, 113.3, 115.4, 118.8, (C=N), 192.0 (C=O). MS (EI): m/z (%)=392 (M+, 44.38),
120.6, 122.8, 124.0, 127.1, 128.1, 128.7, 128.9, 129.5, 181 (100). Anal. calcd for C21H20N4O2S (392.48): C, 64.27;
130.4, 132.2, 133.6, 135.2, 137.6, 140.8, 144.5, 155.8 H, 5.14; N, 14.28; found: C, 64.49; H, 5.26; N, 14.49%.
(aromatic carbons), 166.2 (C=N), 171.4 (C=O). MS (EI):
2-((4,6-Dimethylpyrimidin-2-yl)thio)-N-(3-(((2-hydrox-
m/z (%)=366 (M+, 89.97), 59 (100). Anal. calcd for ynaphthalen-1-yl)methylene) amino)phenyl)acetamide (12b):
C24H18N2O2 (366.42): C, 78.67; H, 4.95; N, 7.65; found: The obtained product separated as yellow crystals, crystalized
C, 79.01; H, 5.12; N, 7.88%.
from n-butanol, m.p. 204–206°C, yield 0.70g (67%). IR ν
N-(3-((2-Hydroxybenzylidene)amino)phenyl)-2-pheny- (cm−1): 3444 (OH), 3294 (NH), 3059–3032 (CH aromatic),
lacetamide (7c): The title compound was obtained as yellow 2997–2920 (CH aliphatic), 1666 (C=O), 1620 (C=N), 1578–
crystals, recrystallized from n-butanol, m.p. 195–197°C, 1535 (C=C). 1H NMR (DMSO-d6, 400MHz): δ 2.35 (s, 6H,
yield 0.61g (78%). IR ν (cm−1): 3450 (OH), 3260 (NH), CH3), 4.09 (s, 2H, CH2), 6.98 (s, 1H, aromatic H), 7.01 (d,
3047–3026 (CH aromatic), 2993–2920 (CH aliphatic), 1661 J=9.20Hz, 1H, aromatic H), 7.34 (t, J=7.20Hz, 1H, aro-
(C=O), 1622 (C=N), 1589–1533 (C=C). 1H NMR matic H), 7.44–7.47 (m, 3H, aromatic H), 7.55 (t, J=7.08Hz,
(DMSO-d6, 400MHz): δ 3.67 (s, 2H, CH2), 6.97–7.00 (m, 1H, aromatic H), 7.76 (br s, 1H, aromatic H), 7.80 (d,
2H, aromatic H), 7.12 (d, J=7.84Hz, 1H, aromatic H), 7.26 J=7.48Hz, 1H, aromatic H), 7.94 (d, J=9.20Hz, 1H, aro-
(t, J=6.40Hz, 1H, aromatic H), 7.32–7.44 (m, 6H, aromatic matic H), 8.45 (d, J=8.44Hz, 1H, aromatic H), 9.61 (s, 1H,
H), 7.49 (d, J=8.20Hz, 1H, aromatic H), 7.67–7.71 (m, 2H, CH=N), 10.41 (br s, 1H, NH, D2O exchangeable), 15.70 (br s,
aromatic H), 8.92 (s, 1H, CH=N), 10.32 (br s, 1H, NH, D2O 1H, OH, D2O exchangeable). 13C NMR (DMSO-d6,
exchangeable), 13.02 (br s, 1H, OH, D2O exchangeable). 100MHz): δ 23.7 (2 CH3), 35.9 (CH2), 108.8, 112.0, 115.0,
13C NMR (DMSO-d6, 100MHz): δ 43.8 (CH2), 112.8, 116.6, 117.6, 120.5, 122.8, 124.1, 127.1, 128.8, 129.5, 130.6,
116.2, 117.1, 118.0, 119.6, 119.7, 127.0, 128.8, 129.6, 130.2, 133.5, 137.7, 140.5, 144.4, 155.6, 167.5, 169.6 (aromatic car-
133.0, 133.8, 136.3, 140.7, 149.0, 160.7 (aromatic carbons), bons), 171.7 (C=N), 193.4 (C=O). MS (EI): m/z (%)=442
163.8 (C=N), 169.8 (C=O). MS (EI): m/z (%)=330 (M+, (M+, 70.74), 153 (100). Anal. calcd for C25H22N4O2S
100). Anal. calcd for C21H18N2O2 (330.39): C, 76.34; H, (442.54): C, 67.85; H, 5.01; N, 12.66; found: C, 67.53; H,
5.49; N, 8.48; found: C, 76.49; H, 5.67; N, 8.67%.
5.24; N, 12.48%.
N-(3-{[(2-Hydroxynaphthalen-1-yl)methylidene]
(2E)-1-{3-[(2-Hydroxybenzylidene)amino]phenyl}-3-
amino}phenyl)-2-phenylacetamide (7d): The product was phenylprop-2-en-1-one (16a): The title compound sepa-
obtained as yellow crystals, recrystallized from n-butanol, rated as pale yellow crystals on cooling the reaction
m.p. 194–196°C, yield 0.72 g (80%). IR ν (cm−1): 3441 mixture, recrystallized from 90% ethanol, m.p. 115–
(OH), 3287 (NH), 3055–3028 (CH aromatic), 2943 (CH 117°C, yield 0.61g (79%). IR ν (cm−1): 3419 (OH), 3062–
aliphatic), 1662 (C=O), 1627 (C=N), 1589–1535 (C=C). 3022 (CH aromatic), 1662 (C=O), 1618 (C=N), 1607–1574
1H NMR (DMSO-d6, 400 MHz): δ 3.69 (s, 2H, CH2), 7.01 (C=C). 1H NMR (DMSO-d6, 400MHz): δ 7.02 (t,
(d, J = 9.16 Hz, 1H, aromatic H), 7.26–7.42 (m, 8H, aro- J=8.12Hz, 2H, aromatic H), 7.44–7.49 (m, 4H, aromatic
matic H), 7.51–7.55 (m, 2H, aromatic H), 7.78–7.81 (m, H), 7.65–7.74 (m, 3H, aromatic H), 7.81 (d, J=15.60Hz,
2H, aromatic H), 7.94 (d, J = 9.24 Hz, 1H, aromatic H), 1H, ethylenic H), 7.93–7.95 (m, 2H, aromatic H), 8.03 (d,
8.45 (d, J = 8.48 Hz, 1H, aromatic H), 9.60 (s, 1H, CH=N), J=15.60Hz, 1H, ethylenic H), 8.09 (d, J=7.44Hz, 1H,
10.35 (br s, 1H, NH, D2O exchangeable), 15.71 (br s, 1H, aromatic H), 8.18 (s, 1H, aromatic H), 9.08 (s, 1H, CH=N),
OH, D2O exchangeable). 13C NMR (DMSO-d6, 100 MHz): 12.90 (br s, 1H, OH, D2O exchangeable). 13C NMR
δ 43.8 (CH2), 108.8, 112.0, 115.0, 117.6, 120.5, 122.8, (DMSO-d6, 100MHz): δ 117.1, 119.7, 119.8, 121.6,
124.0, 127.0, 127.1, 128.71, 128.74, 128.8, 129.5, 129.6, 122.5, 126.7, 127.2, 129.2, 129.4, 129.5, 130.4, 131.2,
130.5, 133.5, 136.2, 137.6, 140.8, 144.5, 155.7 (aromatic 133.2, 134.0, 135.1, 139.3, 144.9, 149.3, 160.8, 165.1
carbons), 170.0 (C=N), 171.6 (C=O). MS (EI): m/z (aromatic carbons), 189.3 (C=N), 192.3 (C=O). MS (EI):
(%) = 380 (M+, 100). Anal. calcd for C25H20N2O2 m/z (%)=327 (M+, 100). Anal. calcd for C22H17NO2
(380.45): C, 78.93; H, 5.30; N, 7.36; found: C, 78.70; H, (327.38): C, 80.71; H, 5.23; N, 4.28; found: C, 80.53; H,
5.49; N, 7.68%.
5.60; N, 4.32%.

Ibrahim et al.
9
(2E)-1-(3-{[(2-Hydroxynaphthalen-1-yl)methylidene] (416.50): C, 69.21; H, 4.84; N, 6.73; found: C, 69.03; H,
amino}phenyl)-3-phenylprop-2-en-1-one (16b): The 4.97; N, 6.94%.
obtained product was filtered while hot and crystallized 1-{3-[(2-Hydroxybenzylidene)amino]phenyl}-3-pheny-
from n-butanol as yellow crystals, m.p. 203–205°C, yield lurea (24a): The title compound separated as yellow crys-
0.66g (74%). IR ν (cm−1): 3414 (OH), 3059–3028 (CH aro- tals, recrystallized from ethanol, m.p. 227–229°C, yield
matic), 1655 (C=O), 1620 (C=N), 1605–1574 (C=C). H 0.51g (65%). IR ν (cm−1): 3290 (OH), 3200, 3125 (2 NH),
1
NMR (DMSO-d6, 400MHz): δ 7.07 (d, J=9.12Hz, 1H, 3059–3035 (CH aromatic), 1732 (C=O), 1647 (NH bend-
aromatic H), 7.38 (t, J=8.00Hz, 1H, aromatic H), 7.49– ing), 1620 (C=N), 1593–1558 (C=C). 1H NMR (DMSO-d6,
7.53 (m, 3H, aromatic H), 7.58 (t, J=8.00Hz, 1H, aromatic 400MHz): δ 6.98–7.05 (m, 4H, aromatic H), 7.27–7.31 (m,
H), 7.70 (t, J=8.00Hz, 1H, aromatic H), 7.81–7.84 (m, 2H, 3H, aromatic H), 7.38 (t, J=7.88Hz, 1H, aromatic H),
ethylenic H and aromatic H), 7.95–7.99 (m, 4H, aromatic 7.41–7.48 (m, 3H, aromatic H), 7.59 (s, 1H, aromatic H),
H), 8.04 (d, J=15.52Hz, 1H, ethylenic H), 8.05 (d, 7.69 (d, J=7.60Hz, 1H, aromatic H), 8.73 (br s, 1H, NH,
J=7.92Hz, 1H, aromatic H), 8.33 (s, 1H, aromatic H), 8.56 D2O exchangeable), 8.81 (br s, 1H, NH, D2O exchangea-
(d, J=8.48Hz, 1H, aromatic H), 9.78 (s, 1H, CH=N), 15.63 ble), 8.94 (s, 1H, CH=N), 13.08 (br s, 1H, OH, D2O
(br s, 1H, OH, D2O exchangeable). 13C NMR (DMSO-d6, exchangeable). 13C NMR (DMSO-d6, 100MHz): δ 111.8,
100MHz): δ 109.2, 121.0, 121.1, 122.3, 122.6, 124.1, 114.8, 117.1, 118.8, 119.7, 122.5, 127.1, 129.3, 129.8,
125.6, 126.8, 127.3, 128.7, 129.1, 129.4, 129.5, 130.6, 130.3, 133.0, 133.8, 136.9, 141.2, 149.1, 153.0 (aromatic
131.3, 133.6, 135.1, 137.6, 138.9, 139.5, 145.0, 145.4, carbons), 160.7 (C=N), 163.8 (C=O). MS (EI): m/z
157.5, 170.4 (aromatic carbons), 189.4 (C=N), 193.3 (%)=331 (M+, 10.43), 93 (100).Anal. calcd for C20H17N3O2
(C=O). MS (EI): m/z (%)=377 (M+, 100). Anal. calcd for (331.38): C, 72.49; H, 5.17; N, 12.68; found: C, 72.68; H,
C26H19NO2 (377.44): C, 82.74; H, 5.07; N, 3.71; found: C, 5.40; N, 12.50%.
82.41; H, 5.39; N, 3.98%.
1-(3-{[(2-Hydroxynaphthalen-1-yl)methylidene]amino}
N-Benzyl-3-((2-hydroxybenzylidene)amino)benzenesul- phenyl)-3-phenylurea (24b): The title compound separated
fonamide (20a): The title product was obtained as pale yel- as yellow crystals, recrystallized from ethanol, m.p. 262–
low crystals, recrystallized from methanol/chloroform 265°C, yield 0.56g (58%). IR ν (cm−1): 3541 (2 NH), 3398
mixture (5:1), m.p. 153–154°C, yield 0.70g (81%). IR ν (OH), 3067 (CH aromatic), 1732 (C=O), 1628 (C=N),
(cm−1): 3475 (OH), 3302 (NH), 3063 (CH aromatic), 2980 1593–1535 (C=C). 1H NMR (DMSO-d6, 400MHz): δ 7.04
(CH aliphatic), 1620 (C=N), 1610 (NH bending), 1570 (d, J=9.16Hz, 1H, aromatic H), 7.18 (t, J=9.16Hz, 1H,
(C=C), 1350, 1150 (SO2). 1H NMR (DMSO-d6, 400MHz): aromatic H), 7.39–7.43 (m, 3H, aromatic H), 7.51–7.57 (m,
δ 4.05 (d, J=5.48Hz, 2H, CH2), 7.00–7.04 (m, 2H, aro- 3H, aromatic H), 7.81–7.90 (m, 4H, aromatic H), 7.96 (d,
matic H), 7.20–7.30 (m, 5H, aromatic H), 7.45 (t, J=9.20Hz, 1H, aromatic H), 8.07 (s, 1H, aromatic H), 8.46
J=7.76Hz, 1H, aromatic H), 7.65–7.66 (m, 2H, aromatic (d, J=8.44Hz, 1H, aromatic H), 9.66 (s, 1H, CH=N), 10.90
H), 7.72–7.74 (m, 3H, aromatic H), 8.23 (t, J=5.72Hz, 1H, (br s, 1H, NH, D2O exchangeable), 10.97 (br s, 1H, NH,
NH, D2O exchangeable), 8.97 (s, 1H, CH=N), 12.62 (br s, D2O exchangeable), 15.66 (br s, 1H, OH, D2O exchangea-
1H, OH, D2O exchangeable). 13C NMR (DMSO-d6, ble). 13C NMR (DMSO-d6, 100MHz): δ 108.9, 113.2,
100MHz): δ 46.6 (CH2), 111.6, 117.2, 117.7, 119.7, 125.6, 116.8, 118.8, 120.6, 121.0, 122.6, 124.1, 125.2, 127.2,
127.9, 128.1, 128.6, 128.7, 129.9, 130.9, 133.0, 136.9, 128.7, 129.3, 129.6, 130.5, 133.6, 137.6, 138.0, 139.2,
137.9, 142.5, 149.4, 160.6, 165.2 (aromatic carbons), 192.5 144.8, 156.1, 158.9 (aromatic carbons), 159.2 (C=N), 171.1
(C=N). MS (EI): m/z (%)=366 (M+, 100). Anal. calcd for (C=O). MS (EI): m/z (%)=410 (M±1, 9.74), 92 (100).
C20H18N2O3S (366.44): C, 65.56; H, 4.95; N, 7.65; found: Anal. calcd for C24H19N4O3 (411.44): C, 75.57; H, 5.02; N,
C, 65.80; H, 5.12; N, 7.83%.
11.02; found: C, 75.79; H, 5.13; N, 11.34%.
N-Benzyl-3-(((2-hydroxynaphthalen-1-yl)methylene)
2-[(4,6-Dimethylpyrimidin-2-yl)sulfanyl]-N-(3-nitro-
amino)benzenesulfonamide (20b): The product separated phenyl)acetamide (10): A suspension of 2-mercapto-
as yellow crystals, recrystallized from n-butanol, m.p. 182– 4,6-dimethylpyrimidine hydrochloride (9) (1.76g,
184°C, yield 0.85g (87%). IR ν (cm−1): 3417 (OH), 3244 10mmol) and potassium carbonate (2.76g, 20mmol) in
(NH), 3059–3028 (CH aromatic), 2935 (CH aliphatic), absolute ethanol (20mL) was heated under reflux for
1
1620 (C=N), 1574 (C=C), 1350, 1150 (SO2). H NMR 30min. Then, 2-Chloro-N-(3-nitrophenyl)acetamide (8)
(DMSO-d6, 400MHz): δ 4.07 (d, J=6.32Hz, 2H, CH2), (2.15g, 10mmol) was added, and the mixture was heated
7.09 (d, J=9.16Hz, 1H, aromatic H), 7.19–7.27 (m, 5H, under reflux for another 3h. The obtained residue was fil-
aromatic H), 7.40 (t, J=7.20Hz, 1H, aromatic H), 7.60 (t, tered and washed several times with water (3×10mL)
J=8.32Hz, 1H, aromatic H), 7.66–7.73 (m, 2H, aromatic and recrystallized from ethanol. The product separated as
H), 7.83–7.90 (m, 3H, aromatic H), 8.00 (d, J=9.16Hz, yellowish-white crystals, m.p. 138–139°C, yield 2.36g
1H, aromatic H), 8.23 (t, J=6.32Hz, 1H, NH, D2O (74%). IR ν (cm−1): 3259 (NH), 3094–3024 (CH aro-
exchangeable), 8.53 (d, J=8.48Hz, 1H, aromatic H), 9.69 matic), 2978–2924 (CH aliphatic), 1678 (C=O), 1585–
1
(s, 1H, CH=N), 15.39 (br s, 1H, OH, D2O exchangeable). 1535 (C=C). H NMR (DMSO-d6, 400MHz): δ 2.32 (s,
13C NMR (CDCl3, 100MHz): δ 47.4 (CH2), 109.1, 118.4, 6H, 2 CH3), 4.09 (s, 2H, CH2), 6.95 (s, 1H, aromatic H),
119.3, 121.1, 123.9, 124.6, 125.5, 127.9, 128.0, 128.4, 7.61 (t, J=8.20Hz, 1H, aromatic H), 7.90–7.93 (m, 2H,
128.7, 129.4, 130.4, 132.9, 136.0, 137.0, 141.7, 147.3, aromatic H), 8.62 (s, 1H, aromatic H), 10.73 (br s, 1H,
157.2, 168.1 (aromatic carbons), 193.3 (C=N). MS (EI): NH, D2O exchangeable). 13C NMR (DMSO-d6, 100MHz):
m/z (%)=416 (M+, 100). Anal. calcd for C24H20N2O3S δ 23.8 (2 CH3), 36.0 (CH2), 113.6, 116.6, 118.2, 125.5,

10
Journal of Chemical Research 00(0)
130.7, 140.6, 148.4, 167.4, 167.9 (aromatic carbons), yield 0.15–0.18g (20%–25%). IR ν (cm−1): 3441 and 3329
169.6 (C=O). MS (EI): m/z (%)=318 (M+, 5.77), 181 (NH2), 3136 (NH), 3059 (CH aromatic), 1720 (C=O), 1630
1
(100). Anal. calcd for C14H14N4O3S (318.35): C, 52.82; H, (NH bending), 1597–1539 (C=C). H NMR (DMSO-d6,
4.43; N, 17.60; found: C, 52.69; H, 4.65; N, 17.87%.
400MHz): δ 5.11 (s, 2H, NH2), 6.19 (dd, J=7.92, 1.16Hz,
N-(3-Aminophenyl)-2-[(4,6-dimethyl pyrimidin-2-yl)sul- 1H, aromatic H), 6.56 (dd, J=8.84, 0.96Hz, 1H, aromatic
fanyl]acetamide (11):Asuspension of 10 (1.02g, 3.23mmol) H), 6.78 (s, 1H, aromatic H), 6.90 (t, J=7.96Hz, 1H, aro-
in ethanol (9mL) was slowly added to a solution of stannous matic H), 6.96 (t, J=7.32Hz, 1H, aromatic H), 7.27 (t,
chloride dihydrate (SnCl2·2H2O) (2.55g, 11.31mmol) and J=8.16Hz, 2H, aromatic H), 7.44 (d, J=7.68Hz, 2H, aro-
37% hydrochloric acid (3mL) while cooling in an ice bath. matic H), 8.36 (s, 1H, NH), 8.54 (s, 1H, NH). Anal. calcd
After 30min, the reaction mixture allowed to reach room for C13H13N3O (227.27): C, 68.70; H, 5.77; N, 18.49; found:
temperature and stirred for a further 48h. After completion C, 68.94; H, 5.83; N, 18.71%.
of the reaction, the solution was diluted with water (100mL)
N-(4-Oxo-4, 5-dihydro-1, 3-thiazol-2-yl)-2-
and neutralized with ammonia. The resulting solution was phenylacetamide (26b): To a continuously stirred and cold
extracted with chloroform, washed with water and dried suspension of pseudothiohydantoin 21 (5.8g, 50mmol) in
over anhydrous sodium sulfate. The obtained aniline deriva- anhydrous pyridine (20mL), phenylacetyl chloride (5.83mL,
tive was crystallized from ethanol.
50mmol) was added dropwise. The mixture was heated for
4h under reflux. The solution turned yellow and changed to
a clear orange solution, which after being cooled to room
temperature was poured onto finely crushed ice. After 12h,
the dark-brown crystals which had separated out were fil-
General procedure for the preparation of
compounds 22a,b
To a suspension of the diphenylurea derivative 21 (0.5g, tered, dried and recrystallized from ethanol/charcoal. The
1.94mmol) in dioxane (10mL), the appropriate acid chlo- product was obtained as reddish brown crystals, m.p. 205–
ride (1.94mmol) was added dropwise while cooling in an 206°C, yield 7.02g (60%). IR ν (cm−1): 3410 (NH), 3028
ice bath. The reaction mixture was stirred at room tempera- (CH aromatic), 2932 (CH aliphatic), 1713 (C=O), 1666
ture for 48h. The obtained solution was poured onto ice/ (C=O), 1624 (NH bending), 1549 (C=C). 1H NMR
water and stirred for 30min. The residue was filtered, (DMSO-d6, 400MHz): δ 3.83 (s, 2H, CH2), 3.86 (s, 2H,
washed with water, dried.
CH2), 7.27–7.36 (m, 5H, aromatic H), 12.82 (br s, 1H, NH).
1-(3-Nitrophenyl)-3-phenylimidazolidine-2,4,5-trione Anal. calcd for C11H10N2O2S (234.27): C, 56.40; H, 4.30; N,
(22a): The title product was separated while hot when the 11.96; found: C, 56.71; H, 4.53; N, 12.19%.
residue was boiled with ethanol as white crystals, m.p.
350–353°C, yield 0.50g (83%). IR ν (cm−1): 3024 (CH aro-
General procedure for the preparation of
compounds 27a–f
matic), 1732 (C=O), 1593–1535 (C=C). 1H NMR
(DMSO-d6, 400MHz): δ 7.47–7.54 (m, 3H, aromatic H),
7.59–7.63 (m, 2H, aromatic H), 7.90–7.97 (m, 2H, aromatic To a mixture of the appropriate aldehyde (2.27mmol) and
H), 8.36–8.39 (m, 2H, aromatic H). Anal. calcd for thiazolidinone derivative 22a,b (2.27mmol) in absolute
C15H9N3O5 (311.25): C, 57.88; H, 2.91; N, 13.50; found: C, ethanol (15mL), fused sodium acetate (0.18g, 2.27mmol)
58.12; H, 3.17; N, 13.79%.
was added. The reaction mixture was heated under reflux
1 - ( 3 - N i t r o p h e n y l ) - 3 - p h e n y l p y r i m i d i n e - for 4h, then transferred into a beaker and left to cool. The
2,4,6(1H,3H,5H)-trione (22b): The title product was sepa- obtained precipitate was filtered, washed, dried and recrys-
rated as buff crystals, recrystallized from ethanol, m.p. tallized from ethanol.
163–165°C, yield 0.50g (79%). IR ν (cm−1): 3093 (CH
N-[5-(2-Hydroxybenzylidene)-4-oxo-4,5-dihydro-1,3-
aromatic), 2970 (CH aliphatic), 1763 (2 C=O), 1686 thiazol-2-yl]benzamide (27a): The title compound was
(C=O), 1570–1531 (C=C). 1H NMR (DMSO-d6, 400MHz): obtained as pale brown crystals, m.p. 243–244°C, yield
δ 4.09 (s, 2H, CH2), 7.30–7.38 (m, 2H, aromatic H), 7.42– 0.46g (62%). IR ν (cm−1): 3387 (OH), 3155 (NH), 3062
7.52 (m, 3H, aromatic H), 7.80–7.86 (m, 2H, aromatic H), (CH aromatic), 1701 (2 C=O), 1628 (NH bending), 1597–
8.28–8.36 (m, 2H, aromatic H). Anal. calcd for C16H11N3O5 1539 (C=C). 1H NMR (DMSO-d6, 400MHz): δ 6.99–7.04
(325.28): C, 59.08; H, 3.41; N, 12.92; found: C, 59.26; H, (m, 2H, aromatic H), 7.35 (t, J=7.24Hz, 1H, aromatic H),
3.56; N, 13.21%.
7.51–7.59 (m, 3H, aromatic H), 7.67 (t, J=7.32Hz, 1H,
1-(3-Aminophenyl)-3-phenylurea (23): A suspension of aromatic H), 8.07 (s, 1H, CH=C), 8.18 (d, J=7.44Hz, 2H,
22a,b (3.23mmol) in ethanol (9mL) was slowly added to a aromatic H), 10.59 (br s, 1H, OH, D2O exchangeable),
solution of stannous chloride dihydrate (SnCl2·2H2O) 13.08 (br s, 1H, NH, D2O exchangeable). 13C NMR
(2.55g, 11.31mmol) and 37% hydrochloric acid (3mL) (DMSO-d6, 100MHz): δ 116.7, 120.2, 120.7, 122.9, 129.1,
while cooling in an ice bath. After 30min, the reaction mix- 129.6, 129.8, 130.0, 133.1, 133.8, 158.0 (aromatic car-
ture had reached room temperature and was then refluxed bons), 169.0, 176.0 (2 C=O). MS (EI): m/z (%)=324 (M+,
for 2h. After completion of the reaction, the solution was 1.38), 77 (100). Anal. calcd for C17H12N2O3S (324.35): C,
diluted with water (100mL) and neutralized with ammonia 62.95; H, 3.73; N, 8.64; found: C, 63.11; H, 3.86; N, 8.88%.
solution. The resulting solution was extracted with chloro-
N-{5-[(2-Hydroxynaphthalen-1-yl)methylidene]-4-oxo-
form, washed with water and dried over anhydrous sodium 4,5-dihydro-1,3-thiazol-2-yl}benzamide (27b): The product
sulfate. The obtained aniline derivative was used without was obtained as dark-brown crystals, m.p. 180–182°C,
purification. The title product separated as a yellow oil, yield 0.62g (73%). IR ν (cm−1): 3483 (OH), 3314 (NH),

Ibrahim et al.
11
3067 (CH aromatic), 1697 (2 C=O), 1628 (NH bending), 135.2 (aromatic carbons), 150.2, 178.9 (2 C=O). Anal.
1578–1531 (C=C). 1H NMR (DMSO-d6, 400MHz): δ 7.28 calcd for C22H16N2O3S (388.44): C, 68.03; H, 4.15; N, 7.21;
(d, J=9.08Hz, 1H, aromatic H), 7.41 (t, J=8.00Hz, 1H, found: C, 68.21; H, 4.33; N, 7.49%.
aromatic H), 7.55–7.67 (m, 2H, aromatic H), 7.72 (t,
N-[4-Oxo-5-(thiophen-2-ylmethylidene)-4,5-dihydro-
J=7.72Hz, 1H, aromatic H), 7.89–7.97 (m, 2H, aromatic 1,3-thiazol-2-yl]-2-phenylacetamide (27f): The product
H), 8.05 (d, J=7.92Hz, 1H, aromatic H), 8.14 (d, was obtained as brown crystals, m.p. 280–281°C, yield
J=7.20Hz, 1H, aromatic H), 8.20–8.22 (m, 2H, aromatic 0.55g (74%). IR ν (cm−1): 3113 (NH), 3028 (CH aromatic),
H), 9.27 (s, 1H, CH=C), 10.94 (br s, 1H, NH), 12.89 (br s, 2908 (CH aliphatic), 1720 (C=O), 1686 (C=O), 1589–1558
1
1H, OH). 13C NMR (DMSO-d6, 100MHz): δ 113.2, 118.6, (C=C). H NMR (DMSO-d6, 400MHz): δ 3.90 (s, 2H,
123.7, 123.8, 127.8, 128.3, 128.6, 128.9, 128.9, 129.0, CH2), 7.28–7.36 (m, 6H, aromatic H and thiophene H),
129.1, 129.6, 129.7, 129.8, 132.1, 132.5, 133.4, 135.7, 7.71 (d, J=3.40Hz, 1H, thiophene H), 8.01 (d, J=4.92Hz,
135.9 (aromatic carbons), 154.5, 172.5 (2 C=O). Anal. 1H, thiophene H), 8.06 (s, 1H, CH=C), 13.11 (br s, 1H, NH,
calcd for C21H14N2O3S (374.41): C, 67.37; H, 3.77; N, 7.48; D2O exchangeable). 13C NMR (DMSO-d6, 100MHz): δ
found: C, 67.12; H, 3.89; N, 7.63%.
43.5 (CH2), 124.1, 127.5, 128.4, 128.9, 129.6, 129.9, 130.0,
N-[4-Oxo-5-(thiophen-2-ylmethylidene)-4,5-dihydro- 133.8, 134.3, 135.8, 138.5 (aromatic carbons and thiophene
1,3-thiazol-2-yl]benzamide (27c): The title compound was carbons), 172.9, 180.4 (2 C=O). Anal. calcd for
obtained as yellowish-green crystals, m.p. 224–226°C, C16H12N2O2S2 (328.40): C, 58.52; H, 3.68; N, 8.53; found:
yield 0.61g (85%). IR ν (cm−1): 3391 (NH), 3028 (CH aro- C, 58.74; H, 3.85; N, 8.79%.
matic), 1724 (C=O), 1697 (C=O), 1647 (NH bending),
1589–1551 (C=C). 1H NMR (DMSO-d6, 400MHz): δ 7.33
(t, J=4.32Hz, 1H, thiophene H), 7.58 (t, J=7.44Hz, 2H,
Biological evaluation
aromatic H), 7.68 (t, J=7.32Hz, 1H, aromatic H), 7.75 (d,
J=3.36Hz, 1H, thiophene H), 8.07–8.09 (m, 2H, CH=C
In vitro MTT cytotoxic activity screening
All target compounds were screened for their cytotoxic
and thiophene H), 8.20 (d, J=7.32Hz, 2H, aromatic H),
activity, at the Confirmatory Diagnostic Unit in VACSERA-
13.13 (br s, 1H, NH, D2O exchangeable). 13C NMR
Egypt, against the brain SNB-75 and the lung HOP-92 can-
cer cell lines as well as normal WI-38 fibroblasts using the
MTT assay according to the reported procedure.28 Sorafenib
(DMSO-d6, 100MHz): δ 122.2, 127.6, 129.2, 129.5, 129.8,
133.9, 134.3, 135.0, 135.9, 137.9 (aromatic carbons and
thiophene carbons), 168.7, 176.0 (2 C=O). Anal. calcd for
C15H10N2O2S2 (314.38): C, 57.31; H, 3.21; N, 8.91; found:
was used as a positive control.
C, 57.60; H, 3.49; N, 9.12%.
Declaration of conflicting interests
N-[5-(2-Hydroxybenzylidene)-4-oxo-4,5-dihydro-1,3-
thiazol-2-yl]-2-phenylacetamide (27d): The product was The author(s) declared no potential conflicts of interest with
respect to the research, authorship and/or publication of this
article.
obtained as light brown crystals, m.p. 267–268°C, yield
0.53g (69%). IR ν (cm−1): 3263 (OH), 3128 (NH), 3032
(CH aromatic), 2927 (CH aliphatic), 1724 (C=O), 1663
(C=O), 1582–1555 (C=C). 1H NMR (DMSO-d6, 400MHz):
δ 3.89 (s, 2H, CH2), 6.94–6.98 (m, 2H, aromatic H), 7.27–
7.37 (m, 6H, aromatic H), 7.45 (d, J=7.68Hz, 1H, aromatic
H), 8.08 (s, 1H, CH=C), 10.54 (br s, 1H, NH, D2O exchange-
able), 13.02 (br s, 1H, OH, D2O exchangeable). 13C NMR
(DMSO-d6, 100MHz): δ 43.5 (CH2), 116.7, 120.2, 120.9,
124.9, 127.5, 128.9, 129.3, 129.9, 130.0, 130.8, 133.0,
134.4 (aromatic carbons), 158.0, 174.0 (2 C=O). Anal.
calcd for C18H14N2O3S (338.38): C, 63.89; H, 4.17; N, 8.28;
found: C, 63.71; H, 4.38; N, 8.05%.
Funding
The author(s) received no financial support for the research,
authorship and/or publication of this article.
ORCID iD
Marwa A Ibrahim
https://orcid.org/0000-0002-8521-3747
Supplemental material
Supplemental material for this article is available online.
N-{5-[(2-hydroxynaphthalen-1-yl)methylidene]-4-oxo-
References
4,5-dihydro-1,3-thiazol-2-yl}-2-phenylacetamide
(27e):
The title compound was obtained as dark-brown crystals,
m.p. 200–201°C (decomposition), yield 0.55g (63%). IR ν
(cm−1): 3395 (OH), 3186 (NH), 3062–3032 (CH aromatic),
2981 (CH aliphatic), 1717 (2 C=O), 1631 (NH bending),
1593–1535 (C=C). 1H NMR (DMSO-d6, 400MHz): δ 3.91
(s, 2H, CH2), 7.22–7.37 (m, 3H, aromatic H), 7.46–7.53 (m,
2H, aromatic H), 7.62–7.74 (m, 2H, aromatic H), 7.87–7.90
(m, 2H, aromatic H), 8.11–8.19 (m, 2H, aromatic H), 9.02
(s, 1H, CH=C), 10.15 (br s, 1H, NH, D2O exchangeable),
13.15 (br s, 1H, OH, D2O exchangeable). 13C NMR
(DMSO-d6, 100MHz): δ 43.5 (CH2), 112.0, 112.6, 114.0,
125.1, 127.1, 127.6, 127.7, 128.3, 128.7, 128.8, 128.9,
129.1, 129.7, 129.9, 130.0, 130.3, 131.1, 131.8, 133.3,
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